Immune checkpoint inhibitors (ICI) represent the cornerstone for the treatment of patients with metastatic clear cell renal cell carcinoma (ccRCC). Despite a favorable response for a subset of patients, others experience primary progressive disease, highlighting the need to precisely understand the plasticity of cancer cells and their cross-talk with the microenvironment to better predict therapeutic response and personalize treatment. Single-cell RNA sequencing of ccRCC at different disease stages and normal adjacent tissue (NAT) from patients identified 46 cell populations, including 5 tumor subpopulations, characterized by distinct transcriptional signatures representing an epithelial-to-mesenchymal transition gradient and a novel inflamed state. Deconvolution of the tumor and microenvironment signatures in public data sets and data from the BIONIKK clinical trial (NCT02960906) revealed a strong correlation between mesenchymal-like ccRCC cells and myofibroblastic cancer-associated fibroblasts (myCAF), which are both enriched in metastases and correlate with poor patient survival. Spatial transcriptomics and multiplex immune staining uncovered the spatial proximity of mesenchymal-like ccRCC cells and myCAFs at the tumor–NAT interface. Moreover, enrichment in myCAFs was associated with primary resistance to ICI therapy in the BIONIKK clinical trial. These data highlight the epithelial–mesenchymal plasticity of ccRCC cancer cells and their relationship with myCAFs, a critical component of the microenvironment associated with poor outcome and ICI resistance. Significance: Single-cell and spatial transcriptomics reveal the proximity of mesenchymal tumor cells to myofibroblastic cancer-associated fibroblasts and their association with disease outcome and immune checkpoint inhibitor response in clear cell renal cell carcinoma.

We report the case of a 45-year-old woman in whom a solitary 5.5cm hepatic tumor was discovered during oncologic surveillance for a papillary thyroid carcinoma diagnosed ten years earlier. Biopsy revealed a tumor cell proliferation with "endocrinoid" morphology and convincing immunohistochemical expression of neuroendocrine markers, initially suggesting a well-differentiated grade 3 neuroendocrine tumor. FDG-PET/CT demonstrated isolated hypermetabolic activity in the liver lesion, with no corresponding uptake on DOTATOC-PET. Following neoadjuvant chemotherapy, the patient underwent segmental liver resection. Histopathological examination of the resected specimen showed a proliferation of monomorphic cells with ovoid nuclei, arranged in a tubulo-solid architecture, with focal areas reminiscent of a "thyroid-like" pattern. Tumor cells exhibited heterogeneous expression of neuroendocrine markers and strong, diffuse positivity for alpha-inhibin. RNA sequencing identified a NIPBL::NACC1 fusion transcript, leading to a revised diagnosis of hepatic carcinoma with NIPBL::NACC1 fusion. This recently described and rare hepatic tumor is challenging to diagnose on biopsy. Histologically, it is characterized by a monomorphic ovoid cell proliferation with a tubulo-solid growth pattern and focal thyroid-like morphology. Neuroendocrine marker expression is variable, but strong and diffuse alpha-inhibin staining is a consistent feature.

Urothelial carcinoma is three to four times more common in men than in women, with a 73-year old mean age at diagnosis which is older than the average age at diagnosis of all cancers. Urothelial carcinoma is rare in people under 40 years of age. Smoking, exposure to industrial chemicals, and family history influence the development of bladder cancer, but age remains one of the most important risk factors. It is well established that women are more likely to be diagnosed with an advanced disease, impacting the prognosis and a higher stage-for-stage mortality compared to men. A gender difference is also observed when considering molecular features; for example, there a higher male/female ratio in Fibroblast Growth Factor Receptor 3 (FGFR3)-mutated bladder cancer. Epidermal Growth Factor Receptor (EGFR) amplifications, which are roughly depicted in 25–50% of urothelial carcinoma, have been correlated with a worse prognosis. Genomic alterations of clinical interest are mainly Human Epidermal Growth Factor Receptor 2 mutations and amplifications, as well as FGFR 3 alterations; however, no EGFR mutation has been routinely reported despite the frequency of its amplifications. Recurrently, no targeted inhibitors have demonstrated a benefit compared to platinum-based chemotherapy. We report a rare case of a 35-year-old woman presenting bone, hepatic, and lymph node metastatic urothelial carcinoma, harboring a deletion of 24 nucleotides in exon 19 of the EGFR gene with a 5-month response to osimertinib, a third-generation EGFR tyrosine kinase inhibitor.

Lung allograft pathology encompasses a wide spectrum of disorders, with new entities and emerging diagnostic technologies. The main goal of this study was to document pathologists’ current global practices and highlight areas of consensus and divergence worldwide. A 24-item survey was distributed to transplant centers and responses were received from 35 specialists (51% European, 49% non-European). Most centers used both surveillance and symptom-driven assessments (77%), mainly with transbronchial biopsies (86%) and bronchoalveolar lavage (83%). Non-European centers were more likely to adopt digital pathology (OR 3.03), to use donor-derived cell-free DNA (dd-cfDNA) (OR 2.94), and supported large airway sampling (OR 2.27). Larger centers used dd-cfDNA (OR 2.75) more frequently and consider large airway sampling (OR 2.18). Responders largely supported standardized reporting (86%), reintroducing grade AX (94%), and independent bronchial lesion scoring (82%). Most endorsed an “indeterminate” category for acute and chronic rejection. These findings reflect evolving practices in the field and will inform the ongoing revision of the Lung Allograft Pathology Working Classification.