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Purpose: Surgical resection with complete tumor excision (R0) provides the best chance of long-term survival for patients with intrahepatic cholangiocarcinoma (iCCA). A non-invasive imaging technology, which could provide quick intraoperative assessment of resection margins, as an adjunct to histological examination, is optical coherence tomography (OCT). In this study, we investigated the ability of OCT combined with convolutional neural networks (CNN), to differentiate iCCA from normal liver parenchyma ex vivo., Methods: Consecutive adult patients undergoing elective liver resections for iCCA between June 2020 and April 2021 (n = 11) were included in this study. Areas of interest from resection specimens were scanned ex vivo, before formalin fixation, using a table-top OCT device at 1310 nm wavelength. Scanned areas were marked and histologically examined, providing a diagnosis for each scan. An Xception CNN was trained, validated, and tested in matching OCT scans to their corresponding histological diagnoses, through a 5 × 5 stratified cross-validation process., Results: Twenty-four three-dimensional scans (corresponding to approx. 85,603 individual) from ten patients were included in the analysis. In 5 × 5 cross-validation, the model achieved a mean F1-score, sensitivity, and specificity of 0.94, 0.94, and 0.93, respectively., Conclusion: Optical coherence tomography combined with CNN can differentiate iCCA from liver parenchyma ex vivo. Further studies are necessary to expand on these results and lead to innovative in vivo OCT applications, such as intraoperative or endoscopic scanning., (© 2023. The Author(s).)

In the future, precision medicine with agents targeting specific genetic alterations will play an important role in bladder cancer. This includes both single genetic alterations (e.g. FGFR3) and gene panel analyses in patients with no further therapeutic options, rare cancer subtypes or unusual clinical courses. These molecular analyses can be carried out on formalin-fixed paraffin-embedded tumor samples and the results should be discussed in interdisciplinary molecular tumor boards in order to either recommend approved targeted therapies or suggest patients for molecular-based clinical trials, compassionate use programs or off-label use of drugs. The remuneration of molecular diagnostics is largely well-represented for the outpatient sector in Germany; however, the covering of treatment costs must currently be approved by the health insurances., (© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged., Aim: Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology., Methods: We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions., Results: A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available., Discussion: So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

Besides evidence- and guideline-based tumor therapy, personalized targeted therapies within study settings or individual experimental settings in advanced cancers without further therapeutic options are emerging. A comprehensive molecular analysis of the tumor in a molecular pathology laboratory is important for all targeted therapy approaches. However, the interpretation of the molecular results is crucial and potential therapeutic conclusions can only be drawn by considering the clinical situation and within a setting of oncological experience. Therefore, the molecular results and their potential impact have to be discussed at a molecular tumor board, an interdisciplinary expert team consisting of clinicians, oncologists, (molecular) pathologists, systems physicians, study teams and where required geneticists. If the molecular tumor board decides a targeted therapeutic approach is appropriate, patients should be enrolled in studies or registries with controlled settings and documentation in order to evaluate the therapeutic concepts. Furthermore, molecular-based individual experimental therapies are possible within extreme clinical situations.

The article describes the tumorigenesis of bladder cancer from a pathological perspective in three dimensions: morphology, genetics and epigenetics. Field cancerization and tumor cell migration/seeding are the two main hypotheses used for explaining synchronous and metachronous tumors in the urinary tract. By detailed histological mapping of completely embedded cystectomy specimens we found a single tumor focus in nearly 2/3 of the bladders accompanied by surrounding preinvasive carcinoma in situ. We substantiated our findings by studies analyzing TP53 mutations and loss of heterozygosity in various tumor sites. Identical TP53 mutations suggested a clonal relationship of the tumor foci. In situ lineage tracing via cytochrome C oxidase and succinate dehydrogenase enzyme histochemistry and subsequent mitochondrial DNA mutation analysis for definitive evidence of a clonal relationship in bladder tumors remained inconclusive. We found indications for both theories but intraurothelial migration/seeding was more prominent.A further mechanism in tumorigenesis is gene inactivation by epigenetic DNA methylation. We analyzed DNA methylation of various genes, which had previously been found by RNA expression analysis to be downregulated in bladder cancer. Most importantly, epigenetically silenced ITIH5 was associated with early relapse in pT1 high grade tumors and functionally showed an enhanced invasive metastatic phenotype in tumor cells, suggesting a putative tumor suppressive role. Thus, epigenetic gene silencing is an additional mechanism of tumorigenesis especially in tumor progression.

Introduction: Urothelial carcinoma of the bladder is known as one of most common malignant tumors in the urogenital tract. Non-muscle invasive bladder cancer (NMIBC) in particular has a high recurrence rate and results in correspondingly high costs for the public health system., Methods: To improve the recurrence rate and the prognosis of NMIBC the diagnosis, resection technique, adjuvant instillation therapy and exact histopathological classification of tumor lesions are indispensable. This article gives an overview on the current developments in this field., Results: The current European Association of Urology (EAU) guidelines and the preliminary version of the German S3 guidelines on bladder cancer list photodynamic diagnosis (PDD) and narrow band imaging (NBI) as diagnostic procedures for tumors of the bladder. The trend for resection of bladder tumors is towards the use of en bloc resection using various techniques. Furthermore, an update of the WHO classification aims at a better identification and prognosis of the different risk groups of NMIBC., Conclusion: The treatment of NMIBC can only be improved by the combination of optimized diagnosis, precise tumor resection, improved adjuvant intravesical therapy and correct histopathological evaluation of tumors.

As even a mere thickening of the urothelium can harbor genetic changes identical to that of low grade papillary urothelial tumors, it is not always possible to clearly recognize a precursor lesion of urothelial carcinoma by routine histological diagnostics. Complementary immunohistochemical and molecular diagnostic methods assist the recognition of these entities. These methods especially help to identify clinically important genetically unstable cells as the hallmark of carcinoma in situ (CIS). Little is known about the clinical significance of the morphological subtypes of CIS, which range from large cell to micropapillary variants. For a better understanding of special types of bladder cancer (e.g. adenocarcinoma and squamous cell carcinoma), it seems to be important to define the phenotype and the molecular pattern of non-urothelial lesions, such as intestinal metaplasia and squamous metaplasia, better and more precisely.

Bladder cancer shows rare variants and special subtypes with diverse prognostic importance and therefore may necessitate different therapeutic approaches. For pathologists it is important to histologically diagnose and specify such variants. Nested variants of urothelial carcinoma with inconspicuous, well-formed tumor cell nests present with an aggressive course. The plasmacytoid variant, which morphologically resembles plasma cells is associated with a shorter survival time and a high frequency of peritoneal metastasis. Micropapillary urothelial carcinoma with small papillary tumor cell islands within artificial tissue retraction spaces and frequent lymphovascular invasion also has a poor prognosis. Other important rare differential variants listed in the World Health Organization (WHO) classification are microcystic, lymphoepithelioma-like, sarcomatoid, giant cell and undifferentiated urothelial carcinomas. Additionally, there are three special types of bladder cancer: squamous cell carcinoma, adenocarcinoma and small cell neuroendocrine carcinoma of the bladder. These tumors are characterized by pure squamous cell or glandular differentiation and are sometimes less responsive to adjuvant (chemo)therapy. Small cell carcinoma of the bladder mimics the neuroendocrine features of its pulmonary counterpart, shows an aggressive course but is sensitive to (neo-)adjuvant chemotherapy. The morphology and histology of the most important variants and special types are discussed in this review.

Cytology in uropathological diagnostics is mainly performed for oncological purposes. The assessment of malignancy by urothelial cell morphology is therefore decisive; however, cytology is only sensitive enough to detect high-grade tumor cells and the different low-grade tumors cannot be reliably diagnosed. Thus, the four-tier classification system of cytological findings (i.e. negative, atypical cells but significance uncertain, suspicious and positive) refers to high-grade tumor cells only. Furthermore, for valid cytological diagnostics not only the cytological specimen but also clinical information on cystoscopy findings and, if applicable, a biopsy should be evaluated together. In difficult differential diagnostic settings, e.g. differentiation between reactive versus neoplastic atypia or difficult to access lesions in the upper urinary tract, additional fluorescence in situ hybridization of cytological preparations might be helpful. At the moment there are no indications for further immunocytology or additional biomarker tests.

The current 2004 WHO classification of bladder tumors categorizes non-invasive and invasive urothelial neoplasms into prognostically relevant groups according to the histopathological cell morphology and underlying genetic changes. Although many parts of the classification have not been changed dramatically, even small changes have caused uncertainty and scepticism among urologists and pathologists in recent years. The following review article is structured into various challenges for urologists and pathologists and provides an overview of rare but clinically relevant subgroups and diagnostics, interpretation of diagnoses and pathological findings with respect to consequences for the daily clinical routine (extended diagnosis, therapy and prognosis).

Patient care with noninvasive or minimally invasive methods is appealing for the patient. It has to be assessed in terms of validity to guarantee improvement of patient care. Urine cytology for the detection of tumour cells can be considered a valid method since its specificity and sensitivity is high when high-grade tumour cells are sought. High-grade tumour cells are considered the clinically most relevant finding in urine specimens. Fluorescent in situ hybridization of interphase nuclei on centromeric and gene loci has been optimized for urothelial carcinoma and increases the sensitivity of tumour findings. It also gives a valid chance to adapt the number of cystoscopies in the follow-up of bladder cancer patients more individually.

Despite considerable advances in recent years in our understanding of the genetic changes occurring in urinary bladder cancer, similar progress in the field of epigenetics has hitherto been lacking. Increasingly, however, focus has shifted in the direction of aberrant DNA methylation as a result of recent studies showing the direct impact of such promoter hypermethylation on the loss of tumor suppressor gene expression and function, therefore potentially affecting tumor genesis and progression. The purpose of this study is the identification and characterization of new DNA methylation markers in urinary bladder cancer, with the expectation that these markers could then be incorporated in a multi-gene panel for clinical use in early cancer detection. In addition, better understanding of the signalling pathways involved will undoubtedly impact the development of new treatment strategies. Potential candidate genes, including the Wnt antagonist SFRP5 among others, will be validated by different epigenetic techniques using invasive and superficial urothelial cell lines as well as tumor and urine samples from bladder cancer patients.

Results of molecular pathology have supported changes in the 2004 WHO classification of urothelial cancer. Since then new molecular data such as the distribution pattern of the fibroblast growth factor receptor 3 (FGFR3) has further supported the principle of low and high grade entities of urothelial carcinoma. Animal experiments with knockout mice and conditional knockout systems reveal important parallels to humans and results emphasize the cellular context as a trigger for malignancy. One special feature of the urothelium is its high protection of the urothelial cells by members of the retinoblastoma gene family, efficiently inhibiting invasion even in the presence of p53 mutations. In search of the tumor stem cell phenotype the basal cell phenotype is the focus of attention providing a high clonogenic potential. At the same time detailed analysis of the distribution of mutations in the mitochondrial genome within the urothelium will help to gain insight into the spreading of normal cell or tumor cell clones. The overall data in urological oncology provide evidence that diagnostic and prognostic tools for urothelial cancer can only be reached with multiparametric approaches.

Background: Bowen's disease and erythroplasia of Queyrat are intraepidermal neoplasias (carcinoma in situ) and are considered as preinvasive types of penile squamous cell carcinoma. The risk of progression to invasive cancer is low and such a process can last up to 20 years., Material and Method: Penis preservation and simultaneous complete excision of the tumour are strongly related to the quality of life of the patients and thereby represent the aim of the therapy. Local excision with reconstructive plastic surgery allows satisfactory aesthetic results without jeopardizing cancer control., Results: The results of this treatment are comparable with those after Nd-YAG laser therapy. Local recurrence occurs in up to 33% also after years irrespective of the surgical strategy chosen., Conclusion: A close follow-up with timely treatment of recurrences allows suitable tumour control without worsening the prognosis and is the most important requirement for an organ-preserving treatment of Bowen's disease.

Testosterone secreting tumours of the adrenal glands are usually adrenal carcinomas or adenomas. Here we report the rare case of an adrenal ganglioneuroma with ectopic Leydig cells, a so-called virilizing adrenal ganglioneuroma. Clinically it is characterized by symptoms of virilization, histologically by the occurrence of a population of eosinophilic cells. In the absence of crystalloids of Reinke this cell population can be identified as Leydig cells based on positive immunohistochemical staining of inhibin and calretinin.

We report a case of multifocal urothelial carcinoma in situ of the left ureter with early stromal invasion and concomitant in situ lesions in bladder, prostate and seminal vesicle. After complete topographical mapping of the cystoprostatovesiculectomy specimen the unusual manifestation of urothelial carcinoma in situ in a seminal vesicle turned out to be a tumour spread via the ductus ejaculatorius into the seminal vesicle. DNA sequencing of the tumour suppressor gene TP53 of different tumour lesions revealed identical wild-type sequences.