Head and neck squamous cell carcinomas (HNSCC) have an overall poor prognosis, especially in locally advanced and metastatic stages. In most cases, multimodal therapeutic approaches are required and show only limited cure rates with a high risk of tumor recurrence. Anti-PD-1 antibody treatment was recently approved for recurrent and metastatic cases but to date, response rates remain lower than 25%. Therefore, the investigation of the immunological tumor microenvironment and the identification of novel immunotherapeutic targets in HNSCC is of paramount importance. In our study, we used tissue samples of n = 116 HNSCC patients for the immunohistochemical detection of the intratumoral and peritumoral expression of T cell exhaustion markers (PD-1, LAG-3, TIM-3) on tumor infiltration leukocytes (TIL), as well as the expression level of stromal senescence markers (IL-8, MMP-3) on tumor-associated fibroblasts. The clinical parameter of the vitamin D serum status as well as the histopathological HPV infection status of the tumor was correlated with the expression rates of the biomarkers and the overall patient survival. An increased peritumoral and intratumoral expression of the biomarkers PD-1 and TIM-3 significantly correlated with improved overall patient survival. A high peritumoral expression of LAG-3 correlated with better overall survival. A positive HPV tumor status correlated with a significantly elevated expression of PD-1 and TIM-3. Biomarkers of stromal senescence showed no influence on the patient outcome. However, the vitamin D serum status showed no influence on patient outcomes or biomarker expressions. Our study identified PD-1, LAG-3, and TIM-3 as promising targets of a therapeutic strategy targeting the tumor microenvironment in HNSCC, particularly among HPV-positive patients, where a higher expression of these checkpoints correlated with an improved overall survival. These findings support the potential of antibodies targeting these immune checkpoints to enhance treatment efficacy, especially in the context of bispecific targeting.

Introduction: TROP2 is a transmembrane glycoprotein implicated in tumor progression and immune regulation across epithelial malignancies and serves as a therapeutic target for antibody -drug conjugates. Its role in the tumor immune microenvironment of head and neck squamous cell carcinoma (HNSCC), particularly in the context of PD-1 blockade, remains insufficiently defined. Methods: TROP2 protein expression was assessed by immunohistochemistry in 47 patients with HNSCC treated with anti -PD-1 therapy, including primary tumors and, in 27 cases, matched recurrent and/or metastatic lesions. Expression was quantified using the immunoreactive score. Tumor-infiltrating immune cells (CD3, CD8, CD4, FOXP3, CCR4, and CD163) were analyzed in intra- and peritumoral compartments. In parallel, transcriptomic data from The Cancer Genome Atlas (TCGA; n = 483) were evaluated to explore associations between TROP2 mRNA expression and immune infiltration signatures. Results: TROP2 expression was detected in 95% of tumors, with more than 80% showing moderate to high levels. Higher TROP2 expression was significantly associated with lower T status and showed a trend toward absence of distant metastasis but was not associated with nodal status, UICC stage, disease setting, or response to PD-1 blockade. Increased intratumoral CCR4+ and CD3+ T-cell infiltration correlated with improved survival. TCGA analysis demonstrated significant associations between TROP2 expression and multiple immune cell populations, including CD8+ and CD4+ T cells, Th2 cells, dendritic cells, macrophages, and TGF-β -related signatures. Discussion: These findings indicate that TROP2 is broadly expressed in HNSCC and linked to distinct immune microenvironment features, supporting its potential as a therapeutic target.

Salivary gland carcinomas are rare, heterogeneous, and often resistant to conventional treatments, highlighting the need for new therapeutic strategies. This retrospective study evaluated the expression of three immunologically relevant biomarkers—PRAME, FOLR1, and CLDN18.2—as potential therapeutic targets in salivary gland carcinomas. Tumor samples from 54 patients with seven histological subtypes treated at Saarland University Medical Center between 2013 and 2023 were analyzed using immunohistochemistry and scored with the Immunoreactive Score. PRAME was strongly expressed in 89% of cases, while FOLR1 and CLDN18.2 showed markedly lower expression at 41% and 6%, respectively. High PRAME expression was significantly associated with the presence of distant metastases, regardless of histological subtype. Patients with low PRAME expression tended to have improved overall survival, as indicated by Kaplan–Meier analysis and Log‐Rank testing. These findings suggest PRAME as a promising immunotherapeutic and diagnostic target for salivary gland carcinomas, particularly through T‐cell‐based therapies already under investigation in other malignancies such as acute myeloid leukemia. Further preclinical studies are needed to validate the functional and therapeutic significance of PRAME, FOLR1, and CLDN18.2 in this context.

Background/Objectives: Noninvasive differentiation of parotid gland tumors remains challenging despite ultrasound being the primary imaging modality for salivary gland lesions. Given its examiner dependence, improving diagnostic consistency and transparency is crucial. We quantified interobserver variability in parotid ultrasound, modeled examiner-specific decision patterns using machine learning surrogates, and tested whether surrogate complexity relates to examiner performance. Methods: In this retrospective, single-center study, six examiners independently rated ultrasound images of 149 parotid tumors using predefined descriptors. Performance was summarized using accuracy and the area under the receiver operating characteristic curve (AUC), with 95% confidence intervals (CIs). AUCs were compared using DeLong tests (Holm-adjusted). Interobserver agreement was assessed using pairwise Cohen’s and global Fleiss’ κ. For each examiner, a decision-tree surrogate was trained from structured descriptors and clinical metadata to reproduce examiner labels and visualize decision pathways; performance was estimated by 5-fold cross-validation. Results: Examiner accuracy ranged from 63.5% to 90.5% and AUC from 0.66 to 0.89 (best 0.89, 95% CI 0.83–0.95); the best performer exceeded the two lowest performers (p < 0.001). Agreement was higher for objective descriptors (size: κ = 0.57–0.97) than for subjective descriptors (echogenicity: κ = 0.11–0.79). Surrogate decision-tree accuracy versus histopathology ranged from 57.2% to 80.0% for unpruned and from 65.1% to 76.5% for pruned models, with high coverage (95.3–98.7%). Tree complexity showed no consistent association with examiner performance. Conclusions: Parotid ultrasound shows substantial interobserver variability. Interpretable surrogates can approximate individual labeling behavior from structured descriptors and clinical metadata, making examiner-dependent decision patterns explicit.

Background: Nodular fasciitis is a benign, singularly occurring nodular fibroblastic/myofibroblastic neoplasia. Due to the rapid growth and cellular atypia, this rare differential diagnosis in the head and neck region can be mistaken for malignant sarcomas. Methods: We present a 40-year-old female patient with an unclear, rough, and poorly displaceable supraclavicular swelling on the right as part of a medical check-up. Sonographically, the lump was poorly circumscribed with little vascularization. A consecutive core needle biopsy of the lesion yielded inconclusive results showing spindle-shaped tumor cells. ⁶⁸Ga-FAPI-PET/CT showed an intensive uptake of the right supraclavicular lesion in addition to postoperative changes in the right tonsil. Subsequent operative partial excision of the lesion confirmed the histopathological diagnosis of nodular fasciitis. Results: Nodular fasciitis is the most prevalent pseudosarcoma found in soft tissues. This case is the first description of ⁶⁸Ga-FAPI-PET/CT in nodular fasciitis. Surgical removal is advised; nevertheless, the tumor frequently diminishes on its own, and recurrence is rare. Extensive surgical therapy is not necessary. Conlcusions: The recognition of nodular fasciitis and its benign characteristics is crucial to prevent diagnostic errors and the subsequent unnecessary operative treatment of the patient.