Digital Pathology (DP) revolutionizes the diagnostic workflow. Digitized scanned slides enhance operational efficiency by facilitating remote access, slide storage, reporting and automated AI image analysis, and enabling collaboration and research. However, substantial upfront and maintenance costs remain significant barriers to adoption. This study evaluates DP’s financial and qualitative value, exploring whether the long-term financial benefits justify investments and addressing implementation challenges in large public and private European laboratory settings. A targeted literature review, semi-structured interviews, surveys, and a net present value (NPV) model were employed to assess DP’s impact on clinical practice and laboratory financials. Qualitative findings validate the key benefits of DP, including optimized workflow, enhanced logistics, and improved laboratory organization. Pathologists reported a smooth integration, improved training, teaching, and research capabilities, and increased flexibility through remote work. Collaboration within multidisciplinary teams was strengthened, while case examination efficiency and access to archival slides were notably improved. Quantitative results indicate that DP demonstrates strong financial potential, achieving cost recovery within 6 years. DP investment results in a 7-year NPV of + €0.21 million (m) driven by increased productivity and diagnosis volumes. Although the high upfront costs for scanners, training, and system integration pose a significant barrier to the adoption of DP, larger institutions are better positioned to leverage economies of scale. This study underscores the importance of sustained financial support to cope with the initial investment and regional collaboration in driving widespread adoption of DP. Expanding reimbursement policies for pathology procedures could significantly reduce financial barriers.

Aim/Introduction: Peptide receptor radionuclide therapy (PRRT) represents a cornerstone of treatment regimens for patients with low proliferative neuroendocrine tumors (NETs). However, in patients experiencing somatostatin receptor–positive NET with higher proliferation rates, a value and potential therapeutic benefit of PRRT as part of multimodal treatment approaches and potentially with addition of radiosensitizing agents has not yet been established. Patients and Methods: In this study, 20 patients with histologically confirmed gastroenteropancreatic (GEP) NET with proliferation rates (Ki67) between 15% and 55% were treated either with PRRT only (n = 10) or with a combination therapy (n = 10) comprising PRRT and capecitabine/temozolomide (CAP/TEM) for at least 2 consecutive cycles. Results: Disease control rate in patients treated with PRRT alone was 60% (40% stable disease and 20% partial response). Strikingly, in patients treated with PRRT in combination with radiosensitization (CAP/TEM), the disease control rate was 90% (20% stable disease and 70% partial response). The median progression-free survival in the PRRT only group was 12 months, whereas the median progression-free survival in the PRRT + CAP/TEM group was 26 months and has not been yet reached for all patients in the group during the observation period. The median disease-specific survival for patients with PRRT alone was 51 months, whereas this end point was not yet reached in the PRRT + CAP/TEM group. Moreover, the PRRT + CAP/TEM group showed a significantly higher reduction of SSTR-PET–based metabolic tumor volume and chromogranin A levels compared with the PRRT only group. Importantly, adverse events of all grades did not differ between both groups. Conclusions: PRRT + CAP/TEM represents a highly promising and well-tolerated therapeutic regimen for patients experiencing somatostatin receptor–positive NET with higher (Ki67 ≥ 15%) proliferation rate. Prospective randomized clinical trials are warranted.

Amyloidoses are a group of diseases characterized by the pathological deposition of non-degradable misfolded protein fibrils, including those associated with plasma cell neoplasias, chronic inflammatory conditions, and age-related disorders, among others. Precise identification of the fibril-forming and thereby amyloidosis type defining protein is crucial for prognosis and correct therapeutic intervention. While immunohistochemistry (IHC) is widely used for amyloid typing, it requires extensive interpretation expertise and can be limited by inconclusive staining results. Thus, mass spectrometry (MS), if available, has been proposed as the preferred method for amyloid typing by international specialized centers (USA, UK) using primarily spectral counts for quantification. Here, we introduce an alternative method of relative quantification to further enhance the accuracy and reliability of proteomic amyloid typing. We analyzed 62 formalin-fixed, paraffin-embedded (FFPE) tissue samples, primarily endomyocardial biopsies, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and employed internal normalization of iBAQ values of amyloid-related proteins relative to serum amyloid P component (APCS) for amyloidosis typing. The APCS method demonstrated robust performance across multiple LC-MS/MS platforms and achieved complete concordance with clear cut IHC typed amyloidosis cases. More importantly, it resolved unclear amyloid cases with inconclusive staining results. Additionally, for samples without a distinct fibril-forming protein identified in the standard procedure, de novo sequencing uncovered immunoglobulin light chain components, enabling the diagnosis of rare AL-amyloidosis subtypes. Finally, we established machine learning approach (XGBoost) achieving 94% accuracy by using ∼160 amyloid-related proteins as input variables. In summary, the iBAQ APCS normalization method extended by de novo sequencing allows robust, accurate, and reliable diagnostic amyloid typing, and can be complemented by an AI-based classification. Careful reviewing of each histological sample and the clinical context, nevertheless, remains indispensable for accurate interpretation.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory disorder characterized by somatic mutations in the UBA1 gene in hematopoietic stem cells and associated with diffuse inflammation and myelodysplastic changes amongst others. Due to unspecific symptoms the diagnosis is challenging, and there is an unmet need for clinical markers to select patients for genetic examination. Sera of 9 patients with confirmed VEXAS syndrome were analyzed for immunoglobulin (Ig)G4 levels. Disease parameters and clinical response to therapy were correlated with IgG4 levels. A histopathological examination was performed on the available samples to exclude IgG4-related autoimmune diseases. In this cohort, 44% of our patients showed markedly elevated serum IgG4 levels. We observed a general trend toward a positive correlation between IgG4 levels and inflammatory markers as well as a correlation with clinical response in one patient. Histopathological analysis showed no evidence of IgG4 related disease. IgG4 levels seem to be elevated in a relevant fraction of patients with VEXAS syndrome. In some cases, this might be misinterpreted as IgG4-related disease, a pitfall clinicians should be aware of. Furthermore, our results warrant the further evaluation of a potential correlation of IgG4 levels with disease activity and severity of inflammation. IgG4 serum levels might be useful in the evaluation of the disease course.

Cholangiocarcinomas are rare but aggressive liver tumors of high lethality with scarce treatment options. Here we report on the follow-up of a patient diagnosed with an intrahepatic cholangiocarcinoma who experienced repeated tumor recurrences including distant metastasis, therefore facing a dismal prognosis. At present, this patient is tumor-free for more than 8 years following repeated surgery and application of two successive personalized vaccines. In-depth functional immune cell analyses revealed a dominant CD4 ⁺ T-cell response against the vaccine antigens with infiltration of the tumor site and immune responses prevailing for years following the last vaccine administration. Additionally, spontaneous tumor neoantigen-specific CD4 ⁺ and CD8 ⁺ T-cell responses have been detected, which might have contributed to the outstanding outcome witnessed in this patient. This case report highlights vaccination strategies targeting non-mutated antigens as well as the increasingly recognized central role of antitumor CD4 ⁺ T cells.

Background: Folate receptor alpha (FRα) is a glycosylphosphatidylinositol-anchored membrane protein encoded by the FOLR1 gene. Its overexpression in various cancers, including ovarian carcinoma, makes it a promising target for antibody-drug conjugates (ADC). Mirvetuximab soravtansine-gynx, an FRα-targeting ADC, has been approved by the FDA and EMA for the treatment of FRα-positive, platinum-resistant ovarian cancer. In the United States, patient selection is tied to the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay, an immunohistochemical (IHC) test that identifies tumors with ≥75% moderate-to-strong membrane staining. However, in the European Union, no specific IHC test is mandated, and alternative antibodies are frequently used in routine pathology, necessitating validation of their diagnostic performance. Methods and Results: We report the results of the first interlaboratory proficiency trial on FRα testing conducted by the German Quality Assurance Initiative in Pathology (QuIP^®). Sixty-eight pathology institutes participated across internal and open trials using a variety of antibodies and staining platforms. The VENTANA FOLR1 RxDx Assay demonstrated the highest reliability, with 83% of participating laboratories achieving a successful result. In contrast, alternative clones such as BN3.2 (Leica/Novocastra) and EPR20277 (Abcam) showed substantially weaker staining intensity, lower concordance with reference values, and success rates of only 22–25%, while other antibodies failed entirely. Problem analysis revealed that failures with the VENTANA FOLR1 (FOLR1-2.1) RxDx Assay were mainly due to interpretative challenges, whereas weak staining was the predominant issue with alternative clones. Participation in a preparatory online seminar improved pass rates, underscoring the importance of training. Conclusions: These findings highlight the critical importance of standardized, validated assays for FRα detection to ensure accurate patient selection for targeted therapies. The study emphasizes the need for further optimization of alternative antibodies before clinical implementation.