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Urothelial carcinoma (UC) is by far the most common malignant neoplasm of the urinary bladder; however, there are both benign and malignant changes of the urothelium which morphologically resemble urothelial carcinomas or other carcinomas of the urinary bladder. Thus, these mimickers can cause problems in the histomorphological diagnosis. This article provides an overview of possible mimickers and pitfalls of bladder cancer as well as practical notes on the diagnostic procedure, partly using case studies., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Bone marrow biopsy (BMB) is a well-established diagnostic tool for various hematological, oncological, and other medical conditions. However, treatment options for geriatric patients (pts) facing these diseases are often constrained. In this single-center, retrospective analysis we assessed the diagnostic value of BMB in geriatric pts aged ≥ 85 years and examined its impact on therapeutic decisions. We examined 156 BMB procedures in 129 pts, extracting data from the electronic patient records and applying descriptive statistical methods. Nearly half of the primary diagnostic procedures (26; 44.1%) resulted in a modification of the initially suspected diagnosis. Notably, 15 (25.4%) of these procedures, led to changes in both the diagnosis and planned interventional treatment. Among the 15 follow-up procedures (36.6%), disease progression was initially suspected based on symptoms, but BMB results excluded such progression. In lymphoma staging biopsies, only 2 (3.6%) prompted a change in therapeutic intervention. Importantly, no BMB-related complications, such as bleeding, infection or nerve damage, were reported. Median survival after BMB was 16.1 months across all pts, yet it varied based on the diagnosis and comorbidity score. The survival of pts with a change in therapy based on BMB results did not significantly differ from those who did not undergo a therapy change. In conclusion, BMB proved to be generally safe and beneficial in this geriatric cancer patient cohort beyond the age of 85 years. However, the advantages of lymphoma staging in this patient population warrant further consideration., (© 2024. The Author(s).)

The management of patients with chronic myeloid leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKIs), which induce deep molecular responses so that treatment can eventually be discontinued, leading to treatment-free remission (TFR) in a subset of patients. Unfortunately, leukemic stem cells (LSCs) often persist and a fraction of these can again expand in about half of patients that attempt TKI discontinuation. In this study, we show that presence of myelofibrosis (MF) at the time of diagnosis is a factor associating with TFR failure. Fibrotic transformation is governed by the action of several cytokines, and interestingly, some of them have also been described to support LSC persistence. At the cellular level, these could be produced by both malignant cells and by components of the bone marrow (BM) niche, including megakaryocytes (MKs) and mesenchymal stromal cells (MSCs). In our cohort of 57 patients, around 40% presented with MF at diagnosis and the number of blasts in the peripheral blood and BM was significantly elevated in patients with higher grade of MF. Employing a CML transgenic mouse model, we could observe higher levels of alpha-smooth muscle actin (α-SMA) in the BM when compared to control mice. Short-term treatment with the TKI nilotinib, efficiently reduced spleen weight and BCR::ABL1 mRNA levels, while α-SMA expression was only partially reduced. Interestingly, the number of MKs was increased in the spleen of CML mice and elevated in both BM and spleen upon nilotinib treatment. Analysis of human CML-vs healthy donor (HD)-derived MSCs showed an altered expression of gene signatures reflecting fibrosis as well as hematopoietic support, thus suggesting MSCs as a potential player in these two processes. Finally, in our cohort, 12 patients qualified for TKI discontinuation, and here we observed that all patients who failed TFR had BM fibrosis at diagnosis, whereas this was only the case in 25% of patients with achieved TFR, further supporting the link between fibrosis and LSC persistence., Competing Interests: TB served as a consultant or speaker at satellite symposia for AstraZeneca, Janssen, Merck, Novartis and Pfizer and received research funding form Novartis and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jacobi, Vieri, Bütow, Namasu, Flüter, Costa, Maié, Lindemann-Docter, Chatain, Beier, Huber, Wagner, Crysandt, Brümmendorf and Schemionek.)

We present the case of a patient with severe complications from mediastinal bleeding after endosonographically guided transbronchial cryobiopsy (EBUS-TBKB) with suspected advanced lymphoma. The EBUS-TBKB is a new effective examination method in interventional pneumology for the diagnosis of diseases with mediastinal lymph node enlargement and intrathoracic tumors, with which large tissue cylinders in the mediastinum can be obtained. Due to the high diagnostic value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the clarification of lymphadenopathy, the examination should not be carried out as a routine application. Indications for a primary EBUS-TBKB arise when there is a suspicion of intrathoracic malignant lymphomas or other rare tumors in which extensive unfragmented tissue material is required for diagnosis. A rare complication that has not yet been described in the literature is a hematomediastinum, so that a careful risk assessment of possible bleeding complications should be carried out before intervention and the more invasive mediastinoscopy can be a safer examination method., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Bacillus Calmette-Guérin instillation after removal of the tumor is the first line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guérin therapy fails in >50% of cases, and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied to isolate 30 samples (25 CIS and 5 muscle controls) from 26 fresh-frozen cystectomy specimens. Targeted next-generation sequencing of 31 genes was performed. The panel comprised genes frequently affected in muscle-invasive bladder cancer of nonpapillary origin, focusing on potentially actionable GAs described to predict response to approved targeted therapies or drugs that are in registered clinical trials. Of CIS patients, 92% harbored at least one potentially actionable GA, which was identified in TP53/cell cycle pathway-related genes (eg, TP53 and MDM2) in 72%, genes encoding chromatin-modifying proteins (eg, ARID1A and KDM6A) in 68%, DNA damage repair genes (eg, BRCA2 and ATM) in 60%, and phosphatidylinositol 3-kinase/mitogen-activated protein kinase pathway genes (eg, ERBB2 and FGFR1) in 36% of the cases. These data might help guide the selection of targeted therapies to be investigated in future clinical CIS trials, and they may provide a basis for future mechanistic studies of urothelial CIS pathogenesis., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

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.

Objectives: In 2004, a novel grading system for papillary non-invasive bladder cancer was introduced; low grade (LG) and high grade (HG) in lieu of the former G1, G2, G3. This change allowed for increased reproducibility as well as diminished interobserver variability in histopathological grading among individual pathologists. Matrix Assisted Laser Desorption/Ionization Time of Flight Imaging Mass Spectrometry (MALDI TOF IMS) was evaluated as an automatic and objective tool to assist grading of urothelial neoplasms and to facilitate accuracy., Design and Methods: To separate G1 (LG, n=27) and G3 (HG, n=21) papillary tumors MALDI TOF IMS was performed using an appropriate algorithm. Thereafter, the automatic assignment of a separate G2 (n=31) group was completed., Results: G1 (LG) and G3 (HG) tumors were separated with an overall cross validation of 97.18%. G2 tumors indicated a true positive rate of 78.3% for LG and 87.5% for HG, respectively., Conclusions: MALDI TOF IMS is a powerful support tool to ascertain pathological diagnosis/grading., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

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.

The nested variant of urothelial carcinoma is a rare urothelial neoplasia which is characterized by relatively bland morphology and early muscle-invasive growth. We report on a 65-year-old male patient with a non-invasive high-grade urothelial lesion (carcinoma in situ and pTa G3). After treatment with BCG an invasive urothelial carcinoma was discovered whereas the carcinoma in situ had disappeared. Examination of the bladder specimen showed a nested-variant urothelial carcinoma. Molecular analyses indicated a de-novo genesis of the invasive urothelial carcinoma.

Urothelial carcinoma comprise a heterogenous group of diseases with very different clinical outcome: 70%-80% of urothelial carcinoma are genetically stable and associated with a favorable prognosis, while 20%-30% are genetically unstable and have a high progression rate. Therefore, the current WHO Classification (2004) reduces the histologic grade to simply 'low grade' and 'high grade'. In addition to TNM classification and histologic grade, genetic factors such as p53 mutations, fibroblast growth factor receptor 3 (FGFR3) and phosphatidylinositol-3-kinase (PIC(3)CA) are relevant in a patient's prognosis.