Background. Fusion involving NTRK1, NTRK2 and NTRK3 are oncogenic driver occurring in several adult and pediatric tumor types. In sarcomas they are mostly found in infantile fibrosarcoma, inflammatory (IFS), inflammatory myofibroblastic tumor (IMT) and in the so-called "NTRK-rearranged spindle cell neoplasm" entity described in the current WHO (2020) classification, including lipofibromatosis-like neural tumor, fibrosarcoma-like and malignant peripheral nerve sheath tumor-like spindle cell neoplasms. Methods. We retrospectively reviewed 92 soft tissue and bone sarcomas diagnosed at the Rizzoli Institute between 2019 and 2023, in which pan-TRK IHC was performed. 17 tumours showed positive staining and were further assessed using FISH for NTRK1, NTRK2, and NTRK3 rearrangements. A subset of 12 cases underwent RNA-based NGS for fusion detection. Results. In total, we collected data from 17 patients who tested positive for pan-TRK antibody and compared pan-TRK IHC and molecular testing for the detection of NTRK rearrangement in sarcomas. FISH analysis detected NTRK rearrangements in 4/17 cases (23.5%), while NGS confirmed NTRK fusions in 3/12 cases (25%). All NTRK fusion-positive cases confirmed by both FISH and NGS showed diffuse pan-TRK staining. Two additional cases exhibited pan-TRK diffuse positivity but were NTRK wild-type by NGS and harboured BCOR::MAML1 and EWSR1::NACC2 fusions, respectively. 1 case with focal positivity by immunohistochemistry and NTRK rearrangement by FISH was not confirmed by NGS. Conclusions. Pan-TRK IHC can be considered an initial screening tool to identify sarcomas potentially harbouring NTRK fusions. However, the presence of diffuse pan-TRK immunoreactivity in NTRK-wild-type tumours highlights the need for cautious interpretation of IHC results. FISH may represent a useful intermediate diagnostic tool when NGS is unavailable but requires cautious interpretation particularly in cases with atypical or isolated signals. NGS-based molecular confirmation remains essential for the definitive identification of NTRK fusions.
Background:Mutations in the isocitrate dehydrogenase (IDH) genes are key biomarkers in intrahepatic cholangiocarcinoma (CCA) and adult-type diffuse gliomas, although real-world adoption of comprehensive molecular diagnostics remains uneven. This review aimed to integrate published evidence, clinical experience, and international guidelines to provide pragmatic recommendations that can standardize IDH testing across healthcare systems. Methods:A multidisciplinary panel synthesized data identified through 10 PICO-driven questions, critically appraised guideline statements from ESMO, EANO, NCCN, and WHO-CNS5, and incorporated insights from clinical evidence on IDH molecular profiling in CCA patients. Recommendations were developed through interactive expert discussion. Results:The panel addressed six issues: (i) positioning of next-generation sequencing (NGS) as a first-line assay; (ii) using liquid biopsy to supplement inadequate or uninformative tissue-based molecular analyses; (iii) tumor-adapted workflows combining immunohistochemistry, PCR, or NGS with large genomic panels; (iv) optimizing pre-analytical management of small biopsies in terms of neoplastic cell abundance and nucleic acid fragmentation to safeguard material for integrated testing; (v) evaluating promising biomarkers based on genome-wide methylation profiling and metabolic imaging in specialized centers; and (vi) novel testing strategies including centralized and decentralized algorithms. In addition, emerging approaches based on digital pathology, teleconsultation, and harmonized reimbursement pathways were discussed. These considerations were distilled into a set of "Golden Rules." Conclusions:Optimized molecular profiling is a cornerstone of precision oncology in IDH-mutant tumors, but the lack of harmonized procedures hinders its widespread implementation in the clinical setting. In intrahepatic CCA, upfront NGS should be prioritized to capture the full spectrum of actionable alterations, whereas in diffuse gliomas IHC for IDH1 p.R132H remains recommended, with PCR or NGS reserved for IHC-negative or equivocal cases. Advanced tools such as genome-wide methylation profiling or metabolic imaging may add value in specialized centers. The consensus-based "Golden Rules" pragmatically support harmonization of diagnostic workflows, reducing technical costs and turnaround time, and promoting equitable access to IDH-directed therapies across diverse healthcare settings.
Tumor-to-tumor metastasis (TTM) refers to a malignant tumor metastasizing to a second, distict tumor. It is a rare phenomenon and the most common donor organs are the lung and breast. Here in, we report a case of TTM metastasis of breast carcinoma metastasizing to an adrenocortical adenoma (ACA) in a 40-year-old woman. To the best of our knowledge, this is the first case in which TTM of breast carcinoma metastasizes to an ACA.
A 60-year-old woman with end-stage fibrosing interstitial lung disease (ILD) underwent bilateral lung transplantation. Systematic histological analysis of the explanted lungs revealed extensive lymphangitic carcinomatosis and hilar lymph node metastases from a previously undiagnosed breast carcinoma. Retrospective imaging review identified a suspicious mammographic finding that had not been further investigated. The patient was later diagnosed with metastatic breast cancer and passed away at 12 months post-transplant. This case emphasizes the challenging diagnosis of neoplasia in end-stage lung disease. The incidence of malignancies in explanted lungs is approximately 1.65%, with metastatic cases being extremely rare. This report underscores the importance of thorough histopathological evaluation of explant lungs, advocating for standardized examination protocols to improve the accuracy and depth of pathological diagnosis.
Pathology education is evolving beyond traditional textbooks and increasingly embracing digital and active learning tools. While passive methods of teaching such as lectures remain dominant, active learning approaches-such as case-based learning, gamification, and technology-enhanced education-are on the rise. Tools like digital microscopy, social media, and resources such as Libre Pathology and pathCast are democratizing access to knowledge, fostering interactivity and accessibility. Quizzes and gaming events have become essential tools in medicine, enhancing learner engagement, honing diagnostic skills, and promoting collaborative learning. Notable examples in pathology include the ESP Pathology Progress Test, the RCPath International Pathology Day Quiz, and interactive events like the ISDP Dermatopathology Olympic Games. Gamification not only boosts motivation but also facilitates the practical application of real-world skills. These innovations are particularly impactful in pathology, where simulated diagnostic challenges offer realistic learning experiences. The inaugural SIAPeC Quiz (2024) demonstrated the efficacy of gamification in pathology education, combining interactive case-based challenges with digital tools to enhance diagnostic skills and engagement among junior pathologists. Featuring a diverse range of questions across histology, pathology, and subspecialties, the event incorporated whole-slide images and challenges that push the boundaries of what can be understood from minimal information (#TooCloseToDiagnose and #TooFarToDiagnose). This gamified format created a supportive environment for learners to experiment and learn from mistakes, fostering critical skills in a dynamic setting.
