https://www.pathologica.it/issue/feedPathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology2025-07-04T11:02:09+00:00Mattia Barbareschipathologica@pacinieditore.itOpen Journal SystemsPathologica - Journal of the Italian Society of Anatomic Pathology and Diagnostic Cytopathology, Italian Division of the International Academy of Pathologyhttps://www.pathologica.it/article/view/1478Consensus document on preoperative diagnostic procedures in breast lesions2025-07-04T08:14:03+00:00Stefano Marlettaxxx@nomail.itIsabella Castellanoxxx@nomail.itFrancesca Caumoxxx@nomail.itCarmen Criscitielloxxx@nomail.itPatrizia Frittellixxx@nomail.itDonatella Santinixxx@nomail.itDaniela Terribilexxx@nomail.itDaniela Bernardixxx@nomail.itMarina Bortulxxx@nomail.itMassimo Calabresexxx@nomail.itGiuseppe Catanutoxxx@nomail.itMaria Grazia Cattanixxx@nomail.itLeopoldo Costarellixxx@nomail.itGiulia D’Amatixxx@nomail.itNicola Fuscoxxx@nomail.itOreste Gentilinixxx@nomail.itMoira Ragazzixxx@nomail.itGianni Saguattixxx@nomail.itAlfredo Santinellixxx@nomail.itCristian Scatenaxxx@nomail.itGrazia Sciancaleporexxx@nomail.itFrancesca Pietribiasixxx@nomail.itAnna Sapinoxxx@nomail.itAntonio Rizzoxxx@nomail.it<p>Currently, percutaneous sampling via core needle or vacuum-assisted biopsy is the primary choice to guide the management of patients with clinical or screen-detected breast lesions. Preoperative biopsies allow physicians to get pathological diagnoses as well as key prognostic and predictive data about the nature of the investigated process. Namely, adequate biopsy sampling is crucial for assigning lesions to one diagnostic category (B1- B5). Similarly, evaluating morphological (histotype, vascular invasion, necrosis, etc.) and immunohistochemical/molecular features (ER, PR, Ki-67, and HER2) is the key to address the most effective therapies, especially in the neoadjuvant setting. The multidisciplinary team should always discuss the results of percutaneous biopsies, whose global integration with clinical and radiological findings will drive the adoption of specific treatment options, particularly for uncertain (B3) and suspicious/malignant (B4-B5) lesions. In the present work, we report a comprehensive overview of breast percutaneous biopsy techniques, diagnostic categories, and multidisciplinary management based on widely acknowledged evidence of good clinical practice</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/998Immune checkpoint inhibitor therapy in metastatic renal cell carcinoma: tumour response and immune-related renal vasculitis following cytoreductive nephrectomy2025-01-30T19:58:24+00:00Ekta Jainektajain86@gmail.comJorge A. Diazjad@ccihsv.comMustafa Gokselmgoksel@uabmc.eduArnab Basuabasu@uabmc.eduCristina Magi-Galluzzicmagigalluzzi@uabmc.edu<p><strong>Objective.</strong> Therapeutic landscape of metastatic renal cell carcinoma (mRCC) has transformed over the last 2 decades, particularly with the advent of immune checkpoint inhibitors (ICI). While ICI offer therapeutic benefits, they can also provoke immune-related adverse events (iRAEs). Vasculitis as a clinical iRAE from ICI is rare in association with RCC treatment.</p> <p><strong>Methods.</strong> This study included patients treated at our institution with ICI for mRCC (2019-2024). We collected clinicopathologic data and type and duration of immunotherapy. Histologic sections of tumors were re-reviewed by two pathologists to determine pathologic response and features of ICI-related renal injuries.</p> <p><strong>Results.</strong> We identified 8 patients (median age 61.5 years) of which six (75%) presented with metastases at multiple sites, while two had recurrent oligometastatic disease post-partial nephrectomy. All patients were treated with ICI for a duration ranging from 6 to 20 months; 7 patients received combination therapy (CT) [iplimumab & nivolumab (n=3), pembrolizumab & lenvatinib (n=2), nivolumab & carbozantinib (n=1), pembrolizumab & axitinib (n=1)], while one received monotherapy (MT) (pembrolizumab). Patients were poor surgical candidates at diagnosis (25% Stage 3, 75% stage 4). Six (75%) patients had clear cell RCC (CCRCC), 2 patients had RCC with papillary and eosinophilic features. Tumor necrosis was noted in 75% of cases. Partial tumor response occurred in 7 (87.5%) patients, with 3 (37.5%) achieving tumor downstaging. One patient showed stable primary disease despite resolution of metastatic burden and none of the patients achieved complete response. Three patients (37.5%) had histopathological confirmed renal iRAEs. Two (25%) patients displayed vascular lymphocytic infiltrates, consistent with medium vessels vasculitis; they received CT for 6 months. One patient, who received CT for 20 months, showed a non-necrotizing granuloma.</p> <p><strong>Conclusions. </strong>This study highlights the potential of ICIs for tumor downstaging and disease control in mRCC, though further investigation is warranted to optimize management of iRAEs and long-term outcomes. ICI-associated renal vasculitis is likely underrecognized and underreported highlighting the need for thorough pathological evaluation of non-neoplastic renal tissue in patients receiving ICI.</p>2025-06-06T00:00:00+00:00Copyright (c) 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1481Homologous recombination deficiency testing in ovarian cancer: the diagnostic experience of a referral Italian institution2025-07-04T09:17:43+00:00Francesco Pepexxx@nomail.itGianluca Russoxxx@nomail.itAmedeo Cefalielloxxx@nomail.itMaria Rosaria Lamiaxxx@nomail.itRoberto Buonaiutoxxx@nomail.itGiuseppina Crimaldixxx@nomail.itClaudia Scimonexxx@nomail.itLucia Palumboxxx@nomail.itGiuseppina Roscignoxxx@nomail.itPaola Parentexxx@nomail.itMaria Chiara De Finisxxx@nomail.itClaudia Marchettixxx@nomail.itPierluigi Giampaolinoxxx@nomail.itCarmine De Angelisxxx@nomail.itRoberto Biancoxxx@nomail.itGiancarlo Tronconexxx@nomail.itUmberto Malapelleumberto.malapelle@unina.it<p><strong>Aims</strong>. Recently, precision medicine has drastically modified clinical paradigm for the clinical stratification of high-grade serous ovarian cancer (HGSOC) patients. International societies approved poly (ADP-ribose) polymerase (PARP) inhibitors (PARPIs) to treat platinumsensitive BRCA1/2 defective HGSOC patients. Beyond BRCA1/2, functional defects in homologous recombination repair (HRR) proteins laid the basis for genomic instability evaluation in HGSOC patients. Given that measurement of homologous recombination deficiency (HRD) is extremely complex molecular analysis is outsourced. Of note, this diagnostic algorithm is affected by inconclusive results and high rejection rates. Here, we review the molecular results of BRCA1/2 and HRD analysis from referral institution in predictive molecular pathology. <br><strong>Methods</strong>. From May 2023 to Jan 2024 molecular records from 147 HGSOC patients simultaneously tested for BRCA1/2 and HRD measurement were inspected. A commercially available next-generation sequencing (NGS) panel (Amoy Diagnostics Co Ltd, Xiamen, Fujian, China) was adopted to internally perform molecular analysis on formalin-fixed paraffin- embedded (FFPE) samples. In a subset of patients clinical records were matched with molecular results. <br><strong>Results</strong>. Overall, 2 out of 147 (1.3%) cases were morphologically classified as inadequate. Simultaneous BRCA1/2 - HRD analysis was successfully assessed in 112 out of 145 (77.2%) patents. Molecular analysis revealed 7 out of 112 (6.2%) and 2 out of 112 (1.8%) pathogenetic or likely pathogenetic (class I-II) and variants of uncertain significance (VUS) (class III) BRCA1/2 molecular alterations, respectively. HRD score was positive in 48 out of 112 (42.8%) HGSOC patients. <br><strong>Conclusions</strong>. HRD testing is a reliable method for the clinical management of HGSOC patients.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1482The routine use of a digital tool for the tumor cell fraction quantification in molecular pathology: an international validation of QuANTUM2025-07-04T09:33:30+00:00Vincenzo L’Imperioxxx@nomail.itGiulia Capitolixxx@nomail.itGiorgio Cazzanigaxxx@nomail.itMauro Manninoxxx@nomail.itFrancesca Bonoxxx@nomail.itDavide Seminatixxx@nomail.itCatarina Eloyxxx@nomail.itJoao Pintoxxx@nomail.itElena Guerini Roccoxxx@nomail.itMatteo Fassanxxx@nomail.itPasquale Pisapiaxxx@nomail.itFrancesco Pepexxx@nomail.itLara Pijuanxxx@nomail.itJordi Temprana-Salvadorxxx@nomail.itAntonio Poloniaxxx@nomail.itSyed Ali Khurramxxx@nomail.itEmanuela Bonoldixxx@nomail.itAlessandro Marandoxxx@nomail.itGiuseppe Perronexxx@nomail.itFabio Pagnixxx@nomail.itPMMP SIAPEC collaboratorsxxx@nomail.it<p><strong>Objective</strong>. The absolute and relative quantification of tumor cell fraction (TCF) in tissue samples for molecular pathology testing is time-consuming and poorly reproducible. <br><strong>Methods</strong>. Here we report the results of an international survey on non-small cell lung cancer (NSCLC), validating the Qupath Analysis of Nuclei from Tumor to Uniform Molecular tests (QuANTUM) automated computational pipeline for TCF quantification. <br><strong>Results</strong>. The TCF obtained with QuANTUM is reliable, as demonstrated by the comparison with the manual counting of cells (ground truth, GT) in cell blocks, small biopsies and surgical specimens (overall correlation of 0.89). The visual evaluation of QuANTUMprocessed images increased the pathologists’ agreement with GT and QuANTUM of +0.16, +0.21, +0.09 and +0.17, +0.29, +0.21 across the three sample types, respectively. An overall increase in cases classified as containing ≥100 tumor cells for all sample types was noted after QuANTUM (from 75 cases, 63% to 96 cases, 80% among cell blocks, p = 0.003). <br><strong>Conclusions</strong>. QuANTUM is an easy-to-use and reliable tool for the TCF assessment and its employment significantly modifies the visual estimation by pathologists, improving the assessment of NSCLC cases for molecular analysis</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1483Histological and proteomic characterization of musculoskeletal amyloidomas2025-07-04T10:08:07+00:00Raffaele Gaetaraffaele.gaeta@med.unipi.itFrancesco Grecoxxx@nomail.itFederica Anastasixxx@nomail.itRodolfo Capannaxxx@nomail.itLiam A. McDonnellxxx@nomail.itAlessandro Franchixxx@nomail.it<p><strong>Introduction</strong>. The term amyloidoma applies to localized deposits of amyloid in the absence of systemic amyloidosis. Skeletal and soft tissue amyloidomas are very rare and the pathogenesis is usually associated with lymphoproliferative disorders (plasmacytomas or plasmacytoid lymphomas) or as a consequence of local chronic inflammation. <br><strong>Methods</strong>. In this paper we report the histological and immunohistochemical features of four cases of musculoskeletal amyloidoma in association with combined laser capture microdissection (LCM) of Congo Red positive regions with a recent microproteomics workflow that improves the sensitivity of the analysis in order to confirm the nature of the protein deposit. <br><strong>Results</strong>. Proteomic techniques allowed to elucidate the nature of the amyloid protein deposit, improving the results obtained by immunohistochemistry (IHC). IHC results were confirmed in two cases while LCM coupled with bottom-up microproteomics was necessary to type the other two cases, for which IHC was inconclusive. <br><strong>Conclusions</strong>. In conclusion, proteomic techniques were thus confirmed as a fundamental tool for the complete investigation of protein deposits.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1251Primary Leiomyosarcoma of Bone: A Clinicopathologic and Immunohistochemical Study of 142 Cases2025-04-23T15:06:49+00:00Elena Bellanelena.bellan@aopd.veneto.itAlberto Righialberto.righi@ior.itMarco Gambarottialberto.righi@ior.itStefania Beninistefania.benini@ior.itDino Gibertonidino.gibertoni@unibo.itMarilena Cesarimarilena.cesari@ior.itGiuseppe Bianchigiuseppe.bianchi@ior.itPiero Piccipiero.picci@ior.itAngelo Paolo Dei Tosangelo.deitos@unipd.itMarta Sbaragliamarta.sbaraglia@aopd.veneto.it<p>Leiomyosarcoma is a rare malignant mesenchymal tumor characterized by smooth muscle differentiation. It typically arises in both visceral and somatic soft tissues, while involvement of bone being exceptionally uncommon. Although primary leiomyosarcoma of bone has been a subject of ongoing debate, the advent of immunohistochemistry has reduced the misclassification of other sarcomas, such as fibrosarcoma and undifferentiated pleomorphic sarcoma, facilitating the accurate identification of true primary LMSB cases. To date, just over 200 well-documented LMSB cases have been published in English-language literature. Despite this, understanding of its clinical behaviour and factors influencing patient outcomes remains limited. In this study, we present the clinical, pathological, and immunohistochemical findings from 142 cases of primary bone leiomyosarcoma including extended follow-up data.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1484KDM6A expression loss is frequent in low grade non-invasive urothelial carcinomas of the urinary bladder2025-07-04T10:14:46+00:00Florian Viehwegerxxx@nomail.itNatalia Gorbokonxxx@nomail.itSeyma Büyücekxxx@nomail.itHenning Plagexxx@nomail.itSebastian Hofbauerxxx@nomail.itKira Furlanoxxx@nomail.itSarah Weinbergerxxx@nomail.itBernhard Rallaxxx@nomail.itAnnika Fendlerxxx@nomail.itNadine Biernathxxx@nomail.itBarbara Erberxxx@nomail.itFlorian Roßnerxxx@nomail.itSimon Schallenbergxxx@nomail.itSefer Elezkurtajxxx@nomail.itMaximilian Lennartzxxx@nomail.itElena Badyxxx@nomail.itClaudia Hube-Maggxxx@nomail.itAndreas H. Marxxxx@nomail.itHenrik Samtlebenxxx@nomail.itMargit Fischxxx@nomail.itMichael Rinkxxx@nomail.itHenrik Zechaxxx@nomail.itMarcin Slojewskixxx@nomail.itKrystian Kaczmarekxxx@nomail.itThorsten Eckexxx@nomail.itStefan Kochxxx@nomail.itNico Adaminixxx@nomail.itRonald Simonr.simon@uke.deGuido Sauterxxx@nomail.itJoachim Weischenfeldtxxx@nomail.itTobias Klattexxx@nomail.itThorsten Schlommxxx@nomail.itDavid Horstxxx@nomail.itMartina Kluthxxx@nomail.itSarah Minnerxxx@nomail.it<p><strong>Objective</strong>. The gene lysine demethylase 6A (KDM6A) located on chromosome Xp11 often shows truncating mutations in urothelial carcinoma. Mutations resulting in protein expression loss can be detected by immunohistochemistry (IHC). <br><strong>Methods</strong>. A tissue microarray with >2,500 bladder tumors was analyzed by IHC. 78 cancers were sequenced for KDM6A. <br><strong>Results</strong>. KDM6A expression loss decreased from 36% of 345 pTaG2 low-grade to 23% of 152 pTaG2 high-grade and 18.5% of 92 pTaG3 tumors (p=0.0004) but not further in pT2-4 cancers (17.2-21.9%). KDM6A staining was unrelated to pT, pN, grade, and overall survival (p>0.1894) in 636 patients with pT2-4 cancers. KDM6A loss was more common in male (22.2%) than in female patients (15.4%; p=0.0067), and in tumors from males with Y-chromosome loss (36.1%) than without Y-loss (16.3%; p<0.0001). A KDM6A loss occurred in all 15 male and in 17 (74%) of 23 female patients with a truncating KDM6A mutation, but only 15 (75%) of 20 male and 17 (81%) of 21 female patients with KDM6A expression loss had a truncating mutation. <br><strong>Conclusions</strong>. KDM6A expression loss is frequent in urothelial carcinoma and mostly due to truncating mutations. KDM6A IHC may be a useful tool for the distinction of neoplastic from non-neoplastic urothelial cells in follow-up examinations of patients with KDM6A deficient cancers.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1393Pathological Anatomy Archives: the need for a paradigm shift2025-06-03T21:21:25+00:00Martina Mandaranomartina.mandarano@unipg.itClaudia Floridiclaudia.floridi@unipg.itCristina Pellicciacristina.pelliccia@unipg.itAngelo Sidoniangelo.sidoni@unipg.it<p>With the advent of personalized medicine, it has become increasingly clear that histological preparations stored in the archives of Pathological Anatomy Departments, from simple "residues" of a diagnostic process, have become containers of large quantities of biopathological information, useful to the patients themselves and to scientific research. For these reasons, taking inspiration from a “near disaster” recently published in Pathologica, we propose a different way of conceiving, managing and protecting these archives.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/869From dominance to decline: can we reverse the trend in small molecule and TKI cancer therapies?2024-12-26T17:09:26+00:00Denis Horgandenishorgan@euapm.euPaul HofmanHOFMAN.P@chu-nice.frDaniel Schneiderdan@npowermedicine.comUmberto Malapelleumberto.malapelle@unina.itVivek SubbiahVivek.Subbiah@sarahcannon.com<p>Over the past two decades, precision oncology has seen unprecedented advances, particularly with the rise of small molecule drugs. These drugs have significantly benefitted cancer patients with somatic genomic alterations, contributing to precision cancer medicine. Despite their early promise, there is a growing concern that major pharmaceutical companies are recently moving away from developing small molecules and tyrosine kinase inhibitors (TKIs) due to market saturation, primary and secondary resistance, and economic factors. The Inflation Reduction Act (IRA) further threatens innovation by reducing incentives for small molecule drug development. Additionally, patient access to comprehensive genomic testing remains a significant barrier. To reverse this trend, a multifaceted approach is urgently needed. Embracing cutting-edge technologies, fostering collaborations, and regulatory innovation are essential. Addressing systemic deficiencies, improving patient access, and ensuring ongoing investment in personalized medicine are crucial for realizing the full potential of small molecule oncology drugs and improving patient outcomes. Collaboration among stakeholders is imperative for advancing effective cancer treatments.</p>2025-05-21T00:00:00+00:00Copyright (c) 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1479Lights and shadows of microsatellite status characterization in gastrointestinal cancers in the era of cancer precision therapy2025-07-04T09:01:25+00:00Jessica Gasparelloxxx@nomail.itVittoria Matilde Pivaxxx@nomail.itValentina Angerillixxx@nomail.itCarlotta Cecconxxx@nomail.itMarianna Sabbadinxxx@nomail.itClaudio Luchinixxx@nomail.itPaola Parentexxx@nomail.itLuisa Toffolattixxx@nomail.itFederica Grilloxxx@nomail.itFrancesca Bergamoxxx@nomail.itUmberto Malapellexxx@nomail.itSara Lonardixxx@nomail.itMatteo Fassanmatteo.fassan@unipd.it<p>The introduction of immunotherapy has dramatically changed the paradigm of solid tumor treatment with the creation of novel therapeutic opportunities even for tumors that currently lack valid therapeutic options in the advanced or metastatic setting. Initially, the role of deficient mismatch repair status (dMMR)/microsatellite instability (MSI) as a predictive biomarker was confined to colorectal cancer. In 2017, MSI/dMMR became the first true agnostic biomarker to stratify patient response to immune checkpoint inhibitors. MSI/ dMMR evaluation is a crucial point in diagnostic-therapeutic decision-making for most gastrointestinal cancer patients and the pathologist must be responsible for the delivery of reliable reporting in this setting. The aim of this review is to summarize the current methods available in routine diagnostics for the evaluation of MSI/dMMR status, their limitations, and potential pitfalls that can be encountered. The authors also give an overview of the role of MSI/dMMR as a prognostic and predictive biomarker in gastrointestinal cancers, with a focus on non-colorectal malignancies.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1102Clinical needs and pathology’s answers in neuroendocrine neoplasms of the lung2025-03-05T16:22:00+00:00Giuseppe Pelosigiuseppe.pelosi@unimi.itAlice Laffialice.laffi@cancercenter.humanitas.itMauro Papottimauro.papotti@unito.itSylvie Lantuejoulsylvie.lantuejoul@lyon.unicancer.frJean-Yves Scoazecjean-yves.scoazec@gustaveroussy.frMaria Gemellimaria.gemelli@multimedica.itRiccardo Ricottariccardo.ricotta@multimedica.itSergio Hararisergio.harari@unimi.itEleonora Duregoneleonora.duregon@unito.itRiccardo Papariccardo.papa@multimedica.itAngelica Sonzogniangelica.sonzogni@istitutotumori.mi.itFabrizio Bianchif.bianchi@operapadrepio.itAntonino Brunoantonino.bruno@multimedica.itBarbara Bassanibarbara.bassani@multimedica.itSilvia Uccellasilvia.uccella@hunimed.euCarlo Carnaghicarlo.carnaghi@humanitascatania.itAlexia Bertuzzialexia.bertuzzi@cancercenter.humanitas.it<p class="p1">Lung neuroendocrine neoplasms (NENs) make up a variegated ensemble of malignancies encompassing typical carcinoid (TC) and atypical carcinoid (AC). These are low to intermediate grade neuroendocrine tumors (NETs), and large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), which are full-fledged high-grade neuroendocrine carcinomas (NECs) showing similar clinical outcomes. Through a peer interaction between oncologist and pathologist, we herein constructed a practical approach based on questioning and answering regarding 8 practical issues aimed to provide shared solutions for clinical decision-making. These issues were itemized as sequential steps guided by clinical reasoning and concerned differential diagnosis, combined subtypes, primary and metastatic tumors, small diagnostic material, predictive biomarkers, tumor staging and, lastly, standardizing terminology. This study takes advantage of the close interaction between oncologists and pathologists as a tool to better delineate the decision-making on lung NENs.</p>2025-06-27T00:00:00+00:00Copyright (c) 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathologyhttps://www.pathologica.it/article/view/1480Invasiveness or growth pattern in urothelial tumours. A perspective to rethink the current WHO classification2025-07-04T09:12:58+00:00Jiyeon Leexxx@nomail.itSangjoon Choixxx@nomail.itGhee Young Kwongeeo@skku.edu<p>According to the current WHO classification, urothelial tumors consist of non-invasive urothelial neoplasms and invasive urothelial carcinoma which is supposed to include all tumors with invasion regardless of extent and pattern. Some pathologists are uncomfortable about such all-inclusive definition of invasive urothelial carcinoma and it is questionable whether invasiveness is a valid defining feature for primary distinction of urothelial tumors. Considering that most pathologists understand urothelial tumors based on the dual-track pathway model, we would like to raise concern that it may be necessary to rethink the validity of the current WHO classification compared to the restructuring into papillary vs non-papillary tumors. In our opinion, such restructuring would align the WHO classification with the pathogenesis model and could clarify the diagnostic terminology regarding invasiveness. The term of urothelial carcinoma in situ may also be reconsidered.</p>2025-07-04T00:00:00+00:00Copyright (c) 2025 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology