Tumor heterogeneity plays a central role in treatment resistance, disease progression, and diagnostic uncertainty. However, it may be overlooked by traditional 2D histology. Accurate 3D assessment of tumor microarchitecture is therefore important for capturing its spatial complexity. Micro-CT, a well-established imaging modality now emerging for high-resolution 3D virtual histology of soft tissues, provides a promising alternative. Combined with radiomics, this technique enables interpretable, quantitative characterization of tumor biology beyond visual inspection. In this study, we analyzed radiomics signatures of a large cohort of thyroid tumors (418 patients) using micro-CT imaging of tissue microarrays. We achieved robust classification of (i) neoplastic versus non-neoplastic thyroid tissues, (ii) papillary thyroid carcinoma versus follicular thyroid neoplasm, and (iii) BRAF V600E mutation status. Shapley additive explanations were used to reveal key visual traits driving these classification decisions. Exploratory analysis in a limited TERT cohort (8 mutated vs 103 wild-type) identified prospective radiomics patterns associated with TERT promoter mutations, suggesting potential surrogate imaging biomarkers that warrant further investigation. Micro-CT radiomics shows promise as a complementary tool for diagnostic classification in thyroid cancer and offers a platform for quantitative 3D tissue characterization pending broader validation.

Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer worldwide. Postoperative radiotherapy (PORT) ± chemotherapy improves outcomes in patients with high- and intermediate-risk pathologic features but is associated with substantial morbidity. While de-escalation strategies have been explored mainly in HPV-positive oropharyngeal cancer, prospective evidence across broader HNSCC populations is lacking. Retrospective evidence suggests that a pathology-driven, tailored PORT strategy may safely reduce treatment volumes while maintaining acceptable oncologic control. This trial prospectively evaluates the safety and efficacy of compartmentalized PORT (COMPORT) of the four most common HNSCC localizations. COMPORT is a multicenter, single-arm phase II trial with Bayesian design that will enroll 50 patients with resected oral cavity, oropharynx, larynx, and hypopharynx HNSCC and an indication for adjuvant PORT, as recommended by a multidisciplinary tumor board. Eligible patients will be treated according to a COMPORT-specific algorithm, omitting low-risk anatomical compartments. In some cases, this results in complete omission of PORT. Primary endpoint is the rate of recurrence in omitted (non-irradiated) compartments within 30 months. Secondary endpoints include loco-regional control, progression-free survival, overall survival, physician-rated toxicity (TAME score), and quality of life (MDADI, EORTC QLQ-C30 and HN43). In this trial, COMPORT will be considered successful if the probability that recurrence rates remain below 18

A 48-year-old woman presented with a submucosal, slow-growing tumor of over 1.5 cm in the left upper lip. The enucleation was performed in local anesthesia and after a curved incision cranial to the tumor. The histopathology showed an encapsulated tumor with three diagnostic components: 1) epithelial (ductal) component forming the inner layer of cysts and tubules, 2) myoepithelial cells as their outer layer and 3) myxoid mesenchymal stroma. The healing was uneventful and only a thin scar on the mucosa was visible in the follow up. Pleomorphic adenoma of the minor salivary gland are less common than those of the major salivary gland, with the upper lip being the second most localisation after the palate. Enucleation is the treatment of choice, with care taken to ensure the pseudocapsule remains intact.

A 48-year-old woman presented with a submucosal, slow-growing tumor of over 1.5 cm in the left upper lip. The enucleation was performed in local anesthesia and after a curved incision cranial to the tumor. The histopathology showed an encapsulated tumor with three diagnostic components: 1) epithelial (ductal) component forming the inner layer of cysts and tubules, 2) myoepithelial cells as their outer layer and 3) myxoid mesenchymal stroma. The healing was uneventful and only a thin scar on the mucosa was visible in the follow up. Pleomorphic adenoma of the minor salivary gland are less common than those of the major salivary gland, with the upper lip being the second most localisation after the palate. Enucleation is the treatment of choice, with care taken to ensure the pseudocapsule remains intact.

Tumor heterogeneity plays a central role in treatment resistance, disease progression, and diagnostic uncertainty. However, it may be overlooked by traditional 2D histology. Accurate 3D assessment of tumor microarchitecture is therefore essential for capturing its spatial complexity. Micro-CT, an emerging imaging modality that offers high-resolution 3D virtual histology of soft tissues, provides a promising alternative. Combined with radiomics—a computational approach for interpretable quantification of tissue phenotypes—this technique enables a deeper understanding of tumor biology beyond visual inspection. In this study, we analyzed a large cohort of thyroid tumors (418 patients) using micro-CT imaging of next-generation tissue microarrays, from which we extracted radiomics features. We achieved robust classification of (i) neoplastic versus non-neoplastic thyroid tissues, (ii) papillary versus follicular thyroid carcinoma, and (iii) BRAF V600E mutation status. Feature interpretation using Shapley additive explanations revealed key visual traits driving these classification decisions. Preliminary results also indicated radiomic patterns associated with TERT promoter mutations, suggesting the existence of potential surrogate imaging biomarkers. Overall, micro-CT radiomics shows strong potential as a complementary tool for improving diagnostic and prognostic accuracy in thyroid cancer and offers a novel platform for quantitative pathology into the 3D spatial complexity of neoplastic tissues. ### Competing Interest Statement The authors have declared no competing interest. Strategic Focus Area Personalized Health and Related Technologies (PHRT) of the Eidgenössischen Technischen Hochschulen [Swiss Federal Institutes of Technology (ETH)]

The diagnosis and prognosis of follicular thyroid neoplasms are based on the identification of capsular and vascular invasion. Although conventional histology allows accurate classification in most cases, its inherent limitations in tissue sampling can result in misjudgment of both the presence and extent of invasion, and occasionally result in diagnostic inaccuracies. Consequently, unexpected tumor recurrence or overtreatment still represent significant clinical challenges. To mitigate these limitations, emerging diagnostic approaches are exploring advanced imaging modalities. X-ray 3D virtual histology has been reported to enable non-destructive and comprehensive sampling of the entire tumor volume embedded in formalin-fixed paraffin-embedded blocks. In thisstudy, the X-ray 3D virtual histology technique is first evaluated by classifying 99 follicular thyroid carcinomas and 31 follicular adenomas, achieving an accuracy of 89.2%. It is then applied to tissue blocks from five relapse cases that were postoperatively diagnosed as adenomas using conventional histology. Three of five tumors exhibited at least one unequivocal focus of vascular invasion, reinforcing that even a single well-defined focus portends significant risk of recurrence and distant metastasis. Although histological confirmation at this stage remained necessary, X-ray 3D virtual histology proved to be a valuable screening method.

Histological analysis is the core of follicular thyroid carcinoma (FTC) classification. The histopathological criteria of capsular and vascular invasion define malignancy and aggressiveness of FTC. Analysis of multiple sections is cumbersome and as only a minute tissue fraction is analyzed during histopathology, under-sampling remains a problem. Application of an efficient tool for complete tissue imaging in 3D would speed-up diagnosis and increase accuracy. We show that X-ray propagation-based imaging (XPBI) of paraffin-embedded tissue blocks is a valuable complementary method for follicular thyroid carcinoma diagnosis and assessment. It enables a fast, non-destructive and accurate 3D virtual histology of the FTC resection specimen. We demonstrate that XPBI virtual slices can reliably evaluate capsular invasions. Then we discuss the accessible morphological information from XPBI and their significance for vascular invasion diagnosis. We show 3D morphological information that allow to discern vascular invasions. The results are validated by comparing XPBI images with clinically accepted histology slides revised by and under supervision of two experienced endocrine pathologists.

Thyroid nodules are a widespread phenomenon, with follicular cell-derived thyroid tumors being the most prevalent type of endocrine tumor, spanning from benign through low grade malignant to aggressive neoplasms with dismal prognosis. In clinical practice, histopathological criteria are primarily used to determine malignancy and aggressiveness. Therefore, accurate classification may result in surgical procedures for diagnostic reasons, associated with an imbalanced risk/benefit ratio. In recent years, the use of integrated proteomic approaches has proven valuable in expanding the molecular understanding of thyroid neoplasms, with implications in classification, yet remains understudied in divergent thyroid nodules. Here we show the delineation of subtype-specific and malignancy-dependent molecular characteristics through integrative proteomic and phosphoproteomic analysis of 53 human thyroid tissues, encompassing five frequent benign and malignant tumors. We found that the (phospho)-proteomic profiles enable a clear stratification of malignant and benign thyroid tissues. The method also performs well in delineating follicular adenoma (FA) and follicular thyroid carcinoma (FTC) samples. Beside the dysregulation of cell cycle control, apoptosis, and metabolic reprogramming associated with tumor development and malignancy, we further report increased alterations within the well-established oncogenic RAS/BRAF/MAPK and AKT/MTOR signaling pathways, which, contrary to the prevailing paradigm, did not clearly differentiate between FTC and papillary thyroid carcinoma (PTC). In addition, activities of ATM, PLK2-3, and GRK5-6 kinases were predicted to be strongly upregulated in malignant subtypes. Together, this study provides an in-depth insight into molecular changes in different thyroid tumor subtypes. These findings highlight the potential of integrated proteomic approaches to refine our understanding of complex diseases like cancer. As such, they offer a pathway to more precise diagnostic and personalized treatment strategies. ### Competing Interest Statement The authors have declared no competing interest.

Advances in laboratory-based X-ray computed tomography (CT) have enabled X-ray 3D virtual histology. This method shows a great potential as a complementary technique to conventional 2D histology where extensive volumetric sampling is necessary. While formalin-fixed paraffin-embedded (FFPE) tissue blocks are the backbone of clinical histology, there exists no generic optimization, and technical study of the X-ray 3D virtual histology of FFPE blocks. X-ray micro-CT of FFPE blocks is studied and optimized in their native state within the cassette to minimize the interference of X-ray 3D virtual histology with clinical workflows and standards, hence facilitating the technology transfer to the clinics. The optimization is carried on the sample positioning, tungsten tubes acceleration voltage, and artifact reduction. Then propagation-based imaging of FFPE blocks is extensively discussed. Hierarchical (local) tomography and laminography are presented as viable approaches for achieving higher spatial resolutions. In the end, future perspectives are given by considering state-of-the-art micro-CT scanners using liquid-metal-jet sources, large-area detectors, and photon counting detectors. The results achieved here are generic and can be applicable to any laboratory-based scanner with a tungsten target source and cone-beam geometry. This article provides a starting point for anyone new to X-ray 3D virtual histology on FFPE blocks, but also serves as a useful source for more experienced users.

Die stomatitis migrans ist eine oft beobachtete benigne Normvariante der Mundschleimhaut mit einer Prävalenz von 1.0–2.5%, wobei sie bei jungen Erwachsenen deutlich höher ist. Frauen sind häufiger betroffen. Die Ätiologie ist unbekannt, kommt aber in gleichen Familien gehäuft vor. Klinisch zeigen sich demarkierte, erythematöse Areale, die teilweise von einem gelblichen Saum umrandet sind.

The radicular cyst is the most common odontogenic cyst and is caused by inflammation. It can become atypically large, although the size of the radiographic osteolysis says nothing about the entity of the lesion. This case shows an unusually large multilocular radicular cyst expanding buccally from tooth 46 in a patient with severe autism who can only be treated under general anesthesia. The clinical and radiological picture as well as the intraoperative situation was more indicative of an aggressive cyst or benign tumor. The lesion was surgically completely removed and the teeth 46, 47 and 48 were extracted because of poor compliance and prognosis. Histopathology revealed a radicular cyst. There were no postoperative complications. After eight months, the lesions had almost completely reossified.

Die radikuläre Zyste ist die häufigste odontogene Zyste, deren Ursprung entzündlich ist. Sie kann ungewöhnlich gross werden, wobei die Grösse der Osteolyse nichts zur Diagnose der Läsion aussagt. Der vorliegende Fall zeigt eine ungewöhnlich grosse nach bukkal aufgeworfene multilokuläre radikuläre Zyste, ausgehend vom Zahn 46. Das klinische und radiologische Bild sowie die intra­ operative Situation deuten auf eine aggressive Zyste oder einen benignen Tumor hin. Die Läsion wurde chirurgisch in toto entfernt, zudem wur­ den die Zähne 46, 47 und 48 wegen der schlech­ten Compliance des Patienten extrahiert. Die His­ topathologie ergab die Diagnose einer radikulären Zyste. Es gab wider Erwarten trotz dem grossen knöchernen Defekt keine postoperativen Kompli­ kationen. Nach acht Monaten war die Läsion wie­ der fast vollständig reossifiziert.

Triple negative breast cancer (TNBC) is typically a high-grade breast cancer with poorest clinical outcome despite available treatment modalities with chemo-, immuno- and radiotherapy. The status of tumor-infiltrating lymphocytes (TILs) is a prognostic factor closely related to programmed death ligand 1 (PD-L1) expressed on T lymphocytes modulating antitumor immunity. Immune-checkpoint inhibitors (ICI) are showing promising results in a subset of breast cancer patients in both neo- and adjuvant settings. Pathologic complete response (pCR) after neoadjuvant treatment was found to be associated with better prognosis. We analyzed the prognostic and predictive significance of PD-L1 (SP142 assay) immunohistochemical expression on TNBC patients' samples as illustrated by pCR with regard to its relation to treatment regimen, stage, BRCA mutational status and outcome. Furthermore, we analyzed a few other clinicopathological parameters such as age, TILs and proliferation index. The study highlighted a positive role of PD-L1 evaluation for personalized pCR probability assessment. Although considerable research was made on comparison of PD-L1 level in TNBC with different patient parameters, to our best knowledge, the relation of PD-L1 status to pCR while taking treatment regimen and stage into consideration was so far not investigated.

Efficacy of pembrolizumab in advanced pretreated NSCLC was documented in prospective trials. We aimed to confirm the benefits of pembrolizumab in daily practice. This study was a retrospective analysis of patients (pts) treated in the Expanded Access Program in Poland. Median of progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Analyses were performed with R 3.6.0 software. A total of 34 pts were qualified to pembrolizumab in second or third line of NSCLC treatment. Poor performance status (ECOG 2) was found in 14.7% of pts, brain and liver metastases were diagnosed in 8.8% and 17.6%, respectively. 38% of pts ended the treatment before radiological assessment mainly due to clinical deterioration. In the landmark of 12 and 24 months 35% and 17.6% pts remained alive. Median PFS and OS were 4.4 months (95% confidence interval [CI]: 3.4–9.0) and 8.2 months (95% CI: 4.1–16.1). Immune related adverse events (irAE) were reported in 23% of pts. No treatment-related deaths were reported. In an univariate analysis an ECOG PS 2 (p < 0.001), tumor diameter of >100 mm (p = 0.019), PD during previous chemotherapy (p = 0.037), platelet count (PLT) >409 109/L (p = 0.011), a neutrophil-to-lymphocyte ratio (NLR) ≥3.1 (p = 0.0001) and platelet-to-lymphocyte ratio (PLR) of >183 (p = 0.018) had a negative impact on PFS. The age, sex, histology, location of metastases, PD-L1 expression, level of tumor-infiltrating lymphocytes and comorbidities had no impact. In terms of OS, an ECOG 2 (p < 0.001), PD during chemotherapy (p = 0.037), lack of irAE (p = 0.026), NLR of ≥3.1 (p < 0.001), PLT of ≥409 109 /L (p = 0.011), and PLR of ≥183 (p = 0.018) were negative prognostic factors. ECOG 2 (hazard ratio [HR] 72.63, 95% CI 6.64–794.4; p <0.001), PD during chemotherapy (HR 8.18, 95% CI 1.32–50.4; p = 0.024), and a PLT >409 109 /L (HR 6.18, 95% CI 1.35–28.32; p = 0.019) were independent prognostic factors for OS in multivariate analysis. Pembrolizumab produces durable benefit in 20% of pts with pretreated NSCLC. Clinical and laboratory factors may help to indicate subgroups likely to benefit. Poor PS and lack of response to previous chemotherapy are major determinants of worse prognosis.

CASE PRESENTATION: A 35-year-old woman without past medical history sought treatment for fatigue and dry cough of 3 weeks' duration. Basic laboratory tests revealed severe anemia. She had no history of bleeding, hemoptysis, dyspnea, or fever. The patient was admitted for RBC transfusion and more extensive diagnostics.

Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors’ own files was conducted to search for “low-grade/uncertain oncocytic tumor,” “oncocytoma,” and “oncocytic carcinoma” in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors’ files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.