Histopathology最新文献

Aims: Ovarian Sertoli-Leydig cell tumor (SLCT) with heterologous rhabdomyosarcoma (RMS) is exceptionally rare. While the presence of heterologous elements in SLCT is highly predictive of an underlying DICER1 mutation, the molecular alterations in these tumors, including in SLCTs with heterologous RMS, remain largely unknown. In this study, we aimed to characterize the clinicopathologic features of these rare tumors, and in a subset of cases, we analyzed in detail their molecular changes to investigate potential recurrent and component-specific genetic alterations.

Methods and results: We report clinicopathologic features of 11 ovarian SLCTs with heterologous RMS (positivity for desmin and myogenin); 10 were in keeping with embryonal and 1 with pleomorphic RMS. The patients showed a bimodal age distribution: seven patients (64%) were aged 33 years or younger (mean 20) and four patients (36%) were aged 52 years or older (mean 60). All tumors were unilateral. In addition to the RMS components, 8 of 11 cases (73%) contained other heterologous elements, including gastrointestinal-type mucinous epithelium (5 cases) and immature cartilage (3 cases). Seven of 11 cases (64%) underwent next-generation sequencing analysis. All tumors tested molecularly (7/7, 100%) harbored hotspot DICER1 mutations. Of these, six cases (86%) also carried a second nonsense or frameshift loss-of-function DICER1 mutation. One case had only a p.D1810Y hotspot mutation and consisted of high-grade sarcoma with focal rhabdomyoblastic differentiation (focal expression of desmin and myogenin) in keeping with pleomorphic RMS; the pleomorphic sarcoma component also exhibited mutation-type p53 expression. In addition to DICER1 mutations, TERT c.-124C>T promoter (4 cases) or TP53 mutations (3 cases) were present in all cases and were mutually exclusive. Component-specific analysis in two cases revealed shared common DICER1 hotspot mutations in both the SLCT and RMS components, supporting a clonal origin. In 1 case, a TERT promoter c.-124C>T somatic mutation was present only in the RMS component. In the other case, the TERT promoter mutation was found in both components, while a BRAF p.V600E mutation was exclusive to the RMS component.

Conclusion: Our study demonstrates that the majority (86%) of SLCTs with heterologous RMS harbor double DICER1 mutations (a hotspot mutation and a nonsense or frameshift loss-of-function mutation), supporting the existing knowledge on DICER1 mutations associated with RMS heterologous elements, the presence of which should trigger genetic counselling. Our findings also suggest that molecular alterations other than DICER1, namely, TERT promoter and TP53 mutations, may contribute to component-specific oncogenic transformation.

RB1 was the first identified tumour suppressor gene, named for its crucial role in opposing retinoblastoma oncogenesis. The RB1 gene encodes the retinoblastoma protein pRB, which is a well-known negative regulator of the cell cycle. However, pRB also contributes to cell differentiation by restricting reprogramming and stem cell properties. Accordingly, RB1 inactivation in tumours can induce phenotypic modifications, contributing to tumour progression. Indeed, RB1 pathogenic alterations, either point mutations or deletions, leading to pRB loss of function are observed in 5% of all human cancers. Mutations are much more prevalent in some histologic subgroups, including retinoblastoma, spindle cell lipoma, neuroendocrine prostate cancer and small cell lung carcinoma. In such entities, molecular investigation of tumour samples and mechanistic studies strongly suggest that early RB1 inactivation contributes not only to dysregulation of cell cycle control, but also to the tumour cell phenotype. Among skin carcinomas, RB1 inactivation is the hallmark of primary cutaneous neuroendocrine carcinoma commonly known as Merkel cell carcinoma (MCC), but it has also been described in other tumours including a subset of squamous cell carcinomas, sebaceous carcinomas and the recently described Wnt/beta-catenin-activated non-pilomatrical carcinomas. In this context, we provide a brief overview of the contribution of RB1 inactivation to oncogenesis and tumour cell phenotypes in general and summarise current knowledge regarding RB1-deficient cutaneous carcinomas, highlighting the potential uses of RB1 pathway characterisation for diagnosis, prognosis and therapeutic purposes.

Approximately 50% of penile squamous cell carcinomas are of the usual (conventional) type, resembling their counterparts in the skin or other organs. The remaining half comprises a heterogeneous group of histological variants, some of which exhibit highly distinctive morphological features. Current classification models recognize more than 14 subtypes of penile squamous cell carcinoma. Pathological guidelines recommend histological subtyping of penile carcinomas in diagnostic reports. This practice is clinically significant because specific subtypes carry distinct prognostic implications. However, diagnostic challenges may arise in certain cases due to overlapping histological features. While most subtypes of penile intraepithelial neoplasia (PeIN) are readily identifiable, a subset of cases presents diagnostic challenges. A notable example is distinguishing benign condylomas from low grade minimally atypical warty PeIN. Among invasive carcinomas, the most significant diagnostic difficulties arise in classifying verruciform tumours, due to their overlapping morphological features. Warty carcinomas may simulate giant condylomas; verrucous carcinoma may simulate giant condylomas or Papillary NOS carcinomas. Conversely, this tumour may be confused with low grade warty carcinomas. With some experience, histological classification using H&E stain is possible in about 70% of the cases. The remainder 30%, however, presents diagnostic difficulties even for experienced pathologists. The use of immunostaining and HPV genotyping are crucial aids in the differential diagnosis. By describing and illustrating in detail their morphological features, suggesting treatment options, and emphasizing diagnostic difficulties in the differential diagnosis, we aimed to assist our colleagues in improving their penile neoplasia classification skills.

We focus in this review on the latest developments on several eosinophilic renal entities, aiming to provide an update on this topic that was previously addressed by the Genitourinary Pathology Society in their consensus papers on existing renal entities, and on novel, emerging, and provisional renal entities, and in the World Health Organization 2022 Classification of Renal Cell Tumours (5th Edition). The scope of this review includes an update on more recently described eosinophilic renal entities, including low-grade oncocytic renal tumour (LOT), eosinophilic vacuolated tumour (EVT), folliculin (FLCN) mutated tumour, succinate dehydrogenase (SDH)-deficient renal cell carcinoma, epithelioid angiomyolipoma/epithelioid PEComa (eAML/ePEComa), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), anaplastic lymphoma kinase (ALK)-rearranged RCC, fumarate hydratase (FH)-deficient RCC, papillary renal neoplasm of reversed polarity (PRNRP), tubulocystic RCC (TC-RCC), and thyroid-like follicular carcinoma of kidney (TLFCK). These renal entities fall within the spectrum of eosinophilic renal tumours, in addition to the more common ones with eosinophilic features that will not be covered in this review, such as clear cell renal RCC, papillary RCC, chromophobe RCC, TFE3 rearranged RCC, and TFEB-altered RCC. Pathologists need to consider these less common renal entities in the differential of any eosinophilic renal tumour to be able to diagnose them for the benefit of their patients. The recent developments and acquired knowledge on newer renal entities with eosinophilic cytoplasm opened insights into the clinical, pathological, immunohistochemical, molecular, epidemiological aspects, and the prognosis of these entities. We emphasize the role of routine morphology, aided by appropriate and select immunohistochemistry, as essential keys for diagnosing eosinophilic renal tumours.

Renal cell carcinoma (RCC) with papillary architecture encompasses a diverse group of renal epithelial tumours. The entity papillary RCC is thought to be the second most common subtype of renal cell carcinoma. Although initially categorized into type 1 and type 2 subtypes based on histology, clinicopathological observations in conjunction with molecular advancements have reshaped the above categorization, suggesting that a significant number of the former type 2 tumours can be reclassified. This review traces the historical classification of papillary RCC, discusses emerging entities and reviews the recently recognized molecularly defined RCCs, highlighting diagnostic challenges, morphologic features and key immunohistochemical and genetic features.

Artificial intelligence (AI) is now a practical, value-generating tool in genitourinary (GU) pathology. Real-world deployments report up to 65% time-savings and multi-million-dollar returns on investment within 3 years at high-volume centres. Across prostate, bladder, renal and testicular systems, contemporary algorithms equal or exceed expert accuracy for cancer detection, grading and prognostication. Foundation models trained on millions of whole-slide images now match specialized organ-specific tools without bespoke tuning. High AI–pathologist concordance is widely regarded as a surrogate marker of safety and clinical acceptability, yet no universally codified regulatory threshold for sensitivity, specificity or concordance has been issued. Because internationally recognized guidelines still omit detailed instructions for safe roll-out and sustained performance, we distilled insights from real-world deployments and pioneering pilot studies into two complementary roadmaps: the nine-step VALIDATED framework, which focuses on governance and safety oversight, and the 11-principle ORCHESTRATE blueprint, which guides day-to-day implementation. By 2030, we anticipate AI will automate ~80% of routine quantification, allowing pathologists to assume the role of diagnostic orchestrators who integrate multimodal data streams, helping offset a ~40% workforce shortfall and reducing inter-observer variability across practice settings. This review distils the evidence, economics and practical guidance required for successful AI adoption in GU pathology. Institutions following the VALIDATED–ORCHESTRATE pathway can harness efficiency gains while maintaining diagnostic excellence and achieving positive ROI within 5 years.

In the past few years, upper tract urothelial carcinoma (UTUC) has moved more towards the centre of interest in uro-oncology. Specific guidelines exist, and although these tumours are still rare, handling becomes more common, especially in centres specialized in this type of tumour. Most of the time, conventional urothelial carcinoma (UC) can be diagnosed, but subtypes of UC as well as other carcinoma types exist, which might be more complicated to report. These other tumour morphologies are rare, but recognizing them is of great importance. With the evolution towards personalized medicine, biomarkers have been found; some are evaluated on a protein level using immunohistochemistry, and some require molecular testing. This review will focus on which marker to take. Additionally, major efforts have been taken in order to characterize UTUC on a molecular basis, with some alterations encountered regularly, but others are less frequent. In order to progress with biomarker identification and hence potential new therapeutic options and personalized patient management, the underlying mechanisms must be understood in detail.

Testicular sex cord-stromal tumours (TSCSTs) represent ~4%–8% of all testicular neoplasms. Most show a Leydig or Sertoli cell phenotype and exhibit benign clinical behaviour. However, a subset of ~10% is malignant and clinically problematic, as TGCTs do not respond to systemic therapy. Classification of TSCSTs has relied on morphology, with several entities being defined based on their resemblance to more common ovarian counterparts (e.g. granulosa cell tumours). In recent years, multiple clinicopathologic and molecular studies have improved our understanding of the mechanisms that underlie pathogenesis and progression in TSCSTs, providing data that can be useful to refine classification and prognostication. In this review, we summarise the major recent advances in TSCSTs, focusing on molecular alterations and biomarkers relevant for diagnosis, classification and prognosis.

A broad spectrum of therapies is available for the management of prostate cancer, ranging from well-established interventions like radical prostatectomy, androgen deprivation therapy (ADT) and radiation therapy (RT), to emerging modalities such as focal ablative treatments and targeted molecular therapies. These therapies can induce profound histologic alterations in both benign and malignant prostate tissue. Hormonal and radiation therapies are particularly known for their distinctive and often extensive morphologic effects, which have been well documented across needle biopsies, transurethral resection of the prostate (TURP) or enucleation specimens and prostatectomy samples. Novel ablative techniques—including cryotherapy, high-intensity focused ultrasound (HIFU), photodynamic therapy (PDT) and interstitial laser thermotherapy—are gaining traction, yet the histologic consequences of these newer modalities are still being characterized. These treatment-induced changes can obscure residual carcinoma, complicate tumour grading and staging and sometimes render traditional parameters such as Gleason scoring unreliable. As therapies evolve, pathologists must remain informed about the spectrum of post-treatment changes to accurately interpret prostate specimens. Diagnostic accuracy hinges not only on recognizing these morphologic effects but also on integrating clinical history, particularly when treatment details are not readily available. This review provides an overview of current and investigational prostate cancer therapies, their histologic impact and practical guidance for post-treatment evaluation.