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Background The purpose of this study was to determine the additional diagnostic value of squamous cell carcinoma antigen (SCC‐Ag) in cervical lymph node fine needle aspiration (FNA) samples for the detection of regional metastases of head and neck squamous cell carcinoma (HNSCC). Methods In 149 FNA samples of 114 patients, SCC‐Ag concentration was retrospectively analyzed and associated with diagnosis to establish a cutoff concentration in relation to sensitivity and specificity of HNSCC detection. Results SCC‐Ag was elevated in lymph nodes from patients with HNSCC compared to lymph nodes from other patients (P < 0.01). With 0.3 μg/L as the cutoff concentration, SCC‐Ag has 96% sensitivity for detecting HNSCC. Conclusions SCC‐Ag in FNA is a reliable test for detecting HNSCC in cervical lymph nodes.

Objective To evaluate expression of potential molecular imaging targets epidermal growth factor receptor (EGFR), glycoprotein nonmetastatic melanoma protein B (GPNMB), and vascular endothelial growth factor (VEGF) in lymph nodes (LNs) with or without head and neck squamous cell carcinoma (HNSCC) metastases after (chemo)radiation. Study Design Retrospective study comparing receptor expression in paired lymph nodes after initial treatment. Setting A tertiary referral hospital. Subjects and Methods Salvage neck dissection specimens of 40 patients treated with (chemo)radiation were selected. LNs that contained viable tumor, reactive changes after initial treatment, and normal LNs were analyzed using immunohistochemically determined H-scores and by calculating sensitivity and specificity rates and positive/negative predictive values (PPVs/NPVs). Results EGFR expression was found in 86% and GPNMB expression in 100% of the LNs with viable tumor. VEGF expression was present in all lymph node types. For EGFR, the sensitivity rate was 86%, and specificity rate was 81%. For GPNMB, these were 100% and 75%, respectively. PPV of EGFR was 61.8% and NPV was 98.2%. These were 56.4% and 100% for GPNMB, respectively. Conclusion In residual or recurrent HNSCC lymph node metastases, both EGFR and GPNMB show tumor-specific expression in immunohistochemistry, which may prove useful in future molecular imaging in salvage neck dissections. Immunohistochemically detected VEGF expression indicates that this target is not feasible for imaging purposes in salvage surgery. Therefore, GPNMB could be a new potential imaging target showing comparable results to EGFR in immunohistochemistry.

Objective To determine the diagnostic value of measuring squamous cell carcinoma antigen (SCC-Ag) and cancer antigen 15-3 (CA15-3) concentrations in fine-needle aspiration (FNA) samples for the detection of squamous cell carcinoma (SCC) metastases in cervical lymph nodes. Study Design A prospective study with patients consecutively included between November 2018 and May 2021. Setting A tertiary head and neck oncologic center. Methods Out of 138 patients, SCC-Ag concentrations were analyzed in 168 FNA cervical lymph node samples and CA15-3 in 152 samples. Results were compared with FNA cytology (FNAC) or definitive histology to establish sensitivity and specificity rates. Results For the detection of cervical SCC lymph node metastases, SCC-Ag measurement had an 89.4% sensitivity and 79.3% specificity at a cutoff concentration of 0.1 µg/L. Measurement of CA15-3 concentration in addition to SCC-Ag concentration did not lead to improved accuracy for the detection of SCC. In histology-confirmed cases, FNAC had an 80.0% sensitivity and 100% specificity, as opposed to 93.3% and 57.1%, respectively, for SCC-Ag. Conclusion Measurement of SCC-Ag concentration for detection of SCC lymph node metastases has a sensitivity at least comparable to FNAC and could be used as a relatively cheap screening tool in samples with nondiagnostic or indeterminate FNAC results or when multiple lymph nodes are sampled. However, SCC-Ag in FNA samples has a lower specificity than FNAC assessed by pathologists experienced in head and neck oncology. Addition of CA15-3 measurement did not lead to improved accuracy.

Objective: To evaluate expression of the potential molecular imaging targets glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) in comparison to classical epidermal growth factor receptor (EGFR) in previously untreated head and neck cancer primary tumors and corresponding lymph node metastases, and in lymph node metastases after initial (chemo)radiotherapy. Methods: Primary tumors and lymph node metastases of 38 patients who underwent primary resection of head and neck squamous cell carcinoma (HNSCC) were selected. In addition, lymph node metastases from salvage surgery after (chemo)radiotherapy from 22 patients with HNSCC were selected. Immunohistochemical staining for EGFR, VEGF and GPNMB was performed, after which protein expression was scored using H-scores (percentage of positive tumor cells multiplied by staining intensity ranging from 0 to 2). Primary tumors and lymph node metastases with an H-score ≥5 were considered positive, after which sensitivity rates were calculated. Groups were compared using the Mann-Whitney U test for non-parametric data with post-hoc Bonferroni corrections. Results: In untreated primary HNSCC the sensitivity was 86.8% for EGFR (median H-score 60), 92.1% for VEGF (median 60), and 100% for GPNMB (median 100). In previously untreated lymph node metastases the sensitivity was 81.6% for EGFR (median 30), 86.8% for VEGF (median 65), and 100% for GPNMB (median 118). In lymph node metastases after initial (chemo)radiotherapy, sensitivity was 86.4% for EGFR (median 95) and 100% for GPMB (median 100). VEGF sensitivity could not reliably be evaluated in these lymph nodes due to nonspecific staining in all tissue slides. GPNMB expression was significantly higher compared to EGFR in untreated primary HNSCC (p = .009 and p &lt; .001, respectively) and lymph node metastases (p &lt; .001 for both). Conclusion: GPNMB shows better tumor-specific receptor expression in both sensitivity and H-scores compared to EGFR and VEGF in immunohistochemistry. VEGF performed comparable to EGFR in untreated HNSCC and lymph node metastases. GPNMB could therefore be a new potential imaging target based on these immunohistochemical results. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Saskia H. Hanemaaijer, Gyorgy B. Halmos, Max J. Witjes, Bernard F.A.M. van der Laan, Rudolf S. Fehrmann, Sjoukje F. Oosting, Boudewijn E. Plaat. Comparison of glycoprotein nonmetastatic melanoma protein b, epidermal growth factor receptor and vascular endothelial growth factor expression in head and neck squamous cell carcinoma, and untreated and residual lymph node metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6261.

Objective: Head and neck squamous cell carcinoma (HNSCC) can intraoperatively be visualized by fluorescence molecular imaging (FMI) using fluorophores conjugated to HNSCC specific antibodies. Currently, the epidermal growth factor receptor (EGFR) is used as a target. Targets more specific for HNSCC would reduce background signal, resulting in a higher tumor to background ratio. We aimed to identify new potential targets for FMI in HNSCC. Methods: Publicly available transcriptomic data were collected. A biostatistical method known as Transcriptional Adaptation to Copy Number Alterations (TACNA) profiling was applied, which captures the downstream effects of copy number alterations (CNAs) on mRNA levels, which we used to predict the overexpression on the protein level. By comparing gene expression profiles of HNSCC and normal oral mucosa, genes overexpressed explicitly in HNSCC were identified. Potential targets were selected based on the degree of overexpression, plasma membrane expression, and cross expression in other tissues in the head and neck region. Next, the expression of potential targets of TACNA results on mRNA level were validated on the protein level and compared to EGFR expression using immunohistochemistry (IHC). Subsequently, paired biopsies of HNSCC, adjacent suspicious mucosa, and healthy mucosa of the same patients were stained. Receptor expression was evaluated using H-scores (i.e., percentage of positive cells combined with staining intensity). Results: TACNA profiling was applied on 111 samples of healthy oral mucosa and 410 HNSCC comparing expression levels of 19,635 genes. The newly identified membrane-bound targets were glucose transporter 1 (GLUT-1), placental cadherin (P-cadherin), and monocarboxylate transporter 1 (MCT-1). The three targets were evaluated by IHC in a total of 31 patients, of which 8 had oropharyngeal, 7 hypopharyngeal, and 16 laryngeal carcinomas. GLUT-1 had a median H-score of 175, P-cadherin 140, and MCT-1 40. GLUT-1 and P-cadherin were significantly higher compared to EGFR, with a median H-score of 90 (p &lt; .001). GLUT-1 receptor expression was also seen on erythrocytes, while P-cadherin expression was seen in the basal layer of normal epithelium. This can complicate its use in FMI. Conclusion: TACNA profiling results were successfully validated in immunohistochemistry as a first step in the search for new specific FMI targets in HNSCC. GLUT-1 and P-cadherin show promising results with significantly higher receptor expression than EGFR. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Bernard F.A.M. van der Laan, Max J.H. Witjes, Sjoukje F. Oosting, Rudolf S. Fehrmann, Boudewijn E. Plaat. Identification of molecular imaging targets specific for head and neck squamous cell carcinoma by transcriptional adaptation to copy number alterations profiling: Digital data translated to protein expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6260.