Dedicated Photon-Counting CT for Detection and Classification of Microcalcifications: An Intraindividual Comparison With Digital Breast Tomosynthesis.

OBJECTIVES: Clinical experience regarding the use of dedicated photon-counting breast CT (PC-BCT) for diagnosis of breast microcalcifications is scarce. This study systematically compares the detection and classification of breast microcalcifications using a dedicated breast photon-counting CT, especially designed for examining the breast, in comparison with digital breast tomosynthesis (DBT). MATERIALS AND METHODS: This is a prospective intraindividual study on women with DBT screening-detected BI-RADS-4/-5 microcalcifications who underwent PC-BCT before biopsy. PC-BCT images were reconstructed with a noninterpolated spatial resolution of 0.15 × 0.15 × 0.15 mm (reconstruction mode 1 [RM-1]) and with 0.3 × 0.3 × 0.3 mm (reconstruction mode 2 [RM-2]), plus thin-slab maximum intensity projection (MIP) reconstructions. Two radiologists independently rated the detection of microcalcifications in direct comparison with DBT on a 5-point scale. The distribution and morphology of microcalcifications were then rated according to BI-RADS. The size of the smallest discernible microcalcification particle was measured. For PC-BCT, the average glandular dose was determined by Monte Carlo simulations; for DBT, the information provided by the DBT system was used. RESULTS: Between September 2022 and July 2023, 22 participants (mean age, 61; range, 42-85 years) with microcalcifications (16 malignant; 6 benign) were included. In 2/22 with microcalcifications in the posterior region, microcalcifications were not detectable on PC-BCT, likely because they were not included in the PC-BCT volume. In the remaining 20 participants, microcalcifications were detectable. With high between-reader agreement (κ > 0.8), conspicuity of microcalcifications was rated similar for DBT and MIPs of RM-1 (mean, 4.83 ± 0.38 vs 4.86 ± 0.35) (P = 0.66), but was significantly lower (P < 0.05) for the remaining PC-BCT reconstructions: 2.11 ± 0.92 (RM-2), 2.64 ± 0.80 (MIPs of RM-2), and 3.50 ± 1.23 (RM-1). Identical distribution qualifiers were assigned for PC-BCT and DBT in 18/20 participants, with excellent agreement (κ = 0.91), whereas identical morphologic qualifiers were assigned in only 5/20, with poor agreement (κ = 0.44). The median size of smallest discernible microcalcification particle was 0.2 versus 0.6 versus 1.1 mm in DBT versus RM-1 versus RM-2 (P < 0.001), likely due to blooming effects. Average glandular dose was 7.04 mGy (PC-BCT) versus 6.88 mGy (DBT) (P = 0.67). CONCLUSIONS: PC-BCT allows reliable detection of in-breast microcalcifications as long as they are not located in the posterior part of the breast and allows assessment of their distribution, but not of their individual morphology.

Diffusion probabilistic versus generative adversarial models to reduce contrast agent dose in breast MRI.

BACKGROUND: To compare denoising diffusion probabilistic models (DDPM) and generative adversarial networks (GAN) for recovering contrast-enhanced breast magnetic resonance imaging (MRI) subtraction images from virtual low-dose subtraction images. METHODS: Retrospective, ethically approved study. DDPM- and GAN-reconstructed single-slice subtraction images of 50 breasts with enhancing lesions were compared to original ones at three dose levels (25%, 10%, 5%) using quantitative measures and radiologic evaluations. Two radiologists stated their preference based on the reconstruction quality and scored the lesion conspicuity as compared to the original, blinded to the model. Fifty lesion-free maximum intensity projections were evaluated for the presence of false-positives. Results were compared between models and dose levels, using generalized linear mixed models. RESULTS: At 5% dose, both radiologists preferred the GAN-generated images, whereas at 25% dose, both radiologists preferred the DDPM-generated images. Median lesion conspicuity scores did not differ between GAN and DDPM at 25% dose (5 versus 5, p = 1.000) and 10% dose (4 versus 4, p = 1.000). At 5% dose, both readers assigned higher conspicuity to the GAN than to the DDPM (3 versus 2, p = 0.007). In the lesion-free examinations, DDPM and GAN showed no differences in the false-positive rate at 5% (15% versus 22%), 10% (10% versus 6%), and 25% (6% versus 4%) (p = 1.000). CONCLUSIONS: Both GAN and DDPM yielded promising results in low-dose image reconstruction. However, neither of them showed superior results over the other model for all dose levels and evaluation metrics. Further development is needed to counteract false-positives. RELEVANCE STATEMENT: For MRI-based breast cancer screening, reducing the contrast agent dose is desirable. Diffusion probabilistic models and generative adversarial networks were capable of retrospectively enhancing the signal of low-dose images. Hence, they may supplement imaging with reduced doses in the future. KEY POINTS: • Deep learning may help recover signal in low-dose contrast-enhanced breast MRI. • Two models (DDPM and GAN) were trained at different dose levels. • Radiologists preferred DDPM at 25%, and GAN images at 5% dose. • Lesion conspicuity between DDPM and GAN was similar, except at 5% dose. • GAN and DDPM yield promising results in low-dose image reconstruction.

Abbreviated MRI for Comprehensive Regional Lymph Node Staging during Pre-Operative Breast MRI.

BACKGROUND: The detection of regional lymph node metastases (LNM), in particular significant LNM (≥N2), is important to guide treatment decisions in women with breast cancer. The purpose of this study was to determine whether a coronal pulse sequence as part of pre-operative breast MRI is useful to identify women without significant LNM. MATERIAL: Retrospective study between January 2017 and December 2019 on 414 consecutive women with breast cancer who underwent pre-operative breast MRI on a 1.5 T system. For lymph node (LN) staging, a coronal pre-contrast non-fat-suppressed T1-weighted TSE sequence was acquired with the system's built-in body coil, covering the chest wall; acquisition time 3:12 min. Two radiologists rated the likelihood of LNM on a 3-point scale (absent/possible/present). Validation was obtained by histology from sentinel LN biopsy, axillary LN dissection, and/or PET/CT. RESULTS: 368/414 women were staged to have no or non-significant LNM (pN0 in 282/414, pN1 in 86/414), and significant LNM (≥pN2) in 46/414. For identification of women with significant LNM, MRI was true-positive in 42/46, false-negative in 4/46, true-negative in 327/368, and false-positive in 41/83, the latter mostly caused by women with N1-disease (38/41), yielding an NPV and PPV for significant LNM of 98.8% [95%-CI: 97.0-100%] and 50.6% [43.1-58.1%], respectively. CONCLUSIONS: A 3 min coronal T1-weighted pulse sequence covering the chest wall as part of pre-operative breast MRI is useful to rule out significant LNM with high NPV. Where MRI staging is positive for significant LNM, additional work-up is indicated to improve the distinction of N1 and N2 disease.

Clinical evaluation of cylindrical regional suppression in dynamic contrast-enhanced breast MRI: An intra-individual comparison study on image quality and lesion conspicuity.

PURPOSE: To evaluate the effect of a cylindrical regional-suppression technique (CREST) on image quality and lesion conspicuity in dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the breast. METHOD: This was a comparative study of 67 women with 44 lesions who underwent breast DCE-MRI with CREST (CREST-DCE) and had a previous DCE-MRI without CREST (conv-DCE) available. Two radiologists assessed image quality parameters and lesion conspicuity using five-point Likert scales. In an intra-individual comparison, the effects of CREST on image quality (strong degradation to strong improvement) were assessed. Moreover, both radiologists identified the post-contrast phase, which benefited the most from using CREST in direct comparison. The statistical analysis included the Wilcoxon signed-rank test. RESULTS: Cardiac motion-rated artefacts were significantly reduced in CREST-DCE compared to conv-DCE (3.6 ± 1.2 [CREST-DCE] vs 2.1 ± 0.8 [conv-DCE], p < 0.001). At the axilla, the visualisation of anatomical structures (3.9 ± 1.0 vs 2.3 ± 1.2, p < 0.001) and the skin contour (4.3 ± 0.8 vs 3.0 ± 1.1, p < 0.001) were significantly improved in CREST-DCE, whereas ghosting artefacts were significantly less pronounced (3.8 ± 1.1 vs 2.4 ± 1.0, p < 0.001). The parasternal region was similarly assessable using both techniques (4.3 ± 1.1 vs 4.2 ± 1.2, p = 0.47). In direct comparison, CREST-DCE images were classified as "improved" in 54/67 and "equivalent" in 13/67 exams. The effects of CREST were found to be most pronounced in the very early post-contrast phase (32/67). The lesion conspicuity was rated similar for CREST and conv-DCE (4.7 ± 0.7 vs 4.8 ± 0.2, p = 0.18). CONCLUSIONS: CREST appears to be an effective tool to reduce cardiac motion-related artefacts and, therefore, may improve image quality in breast DCE-MRI without impairing lesion conspicuity.

Digital breast tomosynthesis-guided vacuum-assisted biopsy of suspicious calcifications at different sites within one breast: Is biopsy of more than one location needed?

OBJECTIVE: To investigate how often biopsy of two sites of morphologically similar or equally suspicious calcifications within the same breast yield differing histopathologic results, and how this may affect clinical management. MATERIALS AND METHODS: We identified patients with two or more sites of calcifications categorized as Breast Imaging Reporting and Data System (BI-RADS) ≥ 4b within the same breast who underwent digital breast tomosynthesis-guided vacuum-assisted biopsy (DBT-guided VAB). We analyzed how often biopsy of two distinct sites yielded the same or differing histopathologic findings. The histopathologic findings were dichotomized into "actionable" and "non-actionable", depending on the respective further management. We then analyzed how often the consecutive management would have been the same or different. RESULTS: Of 206 women undergoing DBT-guided VAB at our institution within 24 months, 21 consecutive patients (54 ± 10.2 years; range: 35-71) underwent DBT-guided VAB of two distinct sites of calcifications. Management of histologic findings was the same (both sites actionable or both sites non-actionable) in 12/21 (57 %), different in the remaining 9/21 patients (43 %). Of the nine patients whose differing histologic findings would have led to different clinical management, 4/9 had a high-risk lesion (atypical ductal hyperplasia n = 3, papilloma with epithelial atypia n = 1) vs benign changes (adenosis n = 4), 2/9 had high-grade DCIS vs benign changes (adenosis n = 1, fat necrosis n = 1), and 3/9 had invasive cancer (luminal A n = 2, luminal B n = 1) with high-grade DCIS vs pure high-grade DCIS. CONCLUSIONS: Multiple sites of calcifications within the same breast, even when morphologically similar or equally suspicious, may represent different histopathologic findings with different clinical management implications. Accordingly, in the presence of suspicious calcifications at multiple distinct sites within the same breast, biopsy of more than one site of calcification should be considered.

Liver diffusion-weighted MR imaging with L1-regularized iterative sensitivity encoding reconstruction based on single-shot echo-planar imaging: initial clinical experience.

To investigate whether combining L1-regularized iterative sensitivity encoding (SENSE) reconstruction and single-shot echo planar imaging (EPI) is useful in hepatic DWI. Single-shot EPI-DWI with L1-regularized iterative SENSE reconstruction (L1-DWI) and conventional parallel imaging-based reconstruction (conv-DWI) in liver MRI were compared in volunteers and patients. For the patient cohort, 75 subjects (60 ± 13 years) with 349 focal liver lesions (FLL) were included. Patient groups A and B were used to reduce acquisition time or improve spatial resolution, respectively. Image parameters were rated on a 5-point scale. The number of FLLs was recorded; in case of discrepancy, the reason for non-detectability was analyzed. In volunteers, higher signal-to-noise ratio (24.4 ± 5.6 vs. 12.2 ± 2.3, p < 0.001 at b = 0; 19.3 ± 2.8 vs. 9.8 ± 1.6, p < 0.001 at b = 800) and lower standard deviation of the apparent diffusion coefficient-values (0.17 vs. 0.20 mm2/s, p < 0.05) were found on L1-DWI compared to conv-DWI. In patients, image ratings were similar for all parameters except for "conspicuity of FLLs" which was rated significantly lower on L1-DWI vs. conv-DWI (4.7 ± 0.6 vs. 4.2 ± 0.9, p < 0.05) in group A. In five patients, 11/349 FLLs were not detectable on L1-DWI, but on conv-DWI. L1-regularized iterative reconstruction of single-shot EPI DWI can accelerate image acquisition or improve spatial resolution. However, our finding that FLLs were non-detectable on L1-DWI warrants further research.

Background parenchymal enhancement in contrast-enhanced MR imaging suggests systemic effects of intrauterine contraceptive devices.

OBJECTIVES: Levonorgestrel-releasing intrauterine contraceptive devices (LNG-IUDs) are designed to exhibit only local hormonal effects. There is an ongoing debate on whether LNG-IUDs can have side effects similar to systemic hormonal medication. Benign background parenchymal enhancement (BPE) in dynamic contrast-enhanced (DCE) MRI has been established as a sensitive marker of hormonal stimulation of the breast. We investigated the association between LNG-IUD use and BPE in breast MRI to further explore possible systemic effects of LNG-IUDs. METHODS: Our hospital database was searched to identify premenopausal women without personal history of breast cancer, oophorectomy, and hormone replacement or antihormone therapy, who had undergone standardized DCE breast MRI at least twice, once with and without an LNG-IUD in place. To avoid confounding aging-related effects on BPE, half of included women had their first MRI without, the other half with, LNG-IUD in place. Degree of BPE was analyzed according to the ACR categories. Wilcoxon-matched-pairs signed-rank test was used to compare the distribution of ACR categories with vs. without LNG-IUD. RESULTS: Forty-eight women (mean age, 46 years) were included. In 24/48 women (50% [95% CI: 35.9-64.1%]), ACR categories did not change with vs. without LNG-IUDs. In 23/48 women (48% [33.9-62.1%]), the ACR category was higher with vs. without LNG-IUDs; in 1/48 (2% [0-6%]), the ACR category was lower with vs. without LNG-IUDs. The change of ACR category depending on the presence or absence of an LNG-IUD proved highly significant (p < 0.001). CONCLUSION: The use of an LNG-IUD can be associated with increased BPE in breast MRI, providing further evidence that LNG-IUDs do have systemic effects. KEY POINTS: • The use of levonorgestrel-releasing intrauterine contraceptive devices is associated with increased background parenchymal enhancement in breast MRI. • This suggests that hormonal effects of these devices are not only confined to the uterine cavity, but may be systemic. • Potential systemic effects of levonorgestrel-releasing intrauterine contraceptive devices should therefore be considered.

Relaxation-Enhanced Angiography without Contrast and Triggering (REACT) for pelvic MR venography in comparison to balanced gradient-echo and T2-weighted spin-echo techniques.

RATIONALE AND OBJECTIVES: To evaluate the imaging capabilities of the REACT pulse sequence in pelvic venous vessels compared to conventional non-contrast pulse sequences. MATERIALS AND METHODS: In addition to routine MRI venography, non-contrast enhanced REACT pulse sequence was performed in 4 healthy volunteers and 21 patients with suspected or known deep venous thrombosis and post thrombotic syndrome. Acquired images were independently interpreted by two MRI radiologists. The sequence performance was subjectively evaluated on a four-point scale regarding the delineation of small peripheral, midsize and large proximal venous vessels, the imaging of vascular pathologies, and the degradation due to artifacts. To evaluate statistical differences in diagnostic accuracy Friedman's test with Dunn's correction was used. RESULTS: REACT depicted the peripheral veins superior to bTFE and T2-TSE with an average score of 3.39 compared to 2.33 in bTFE and 1.77 in T2-TSE. In midsize vessels REACT performed significantly better than T2-TSE (1.94) and bTFE (2.68) with a score of 3.64. For the large proximal vessels REACT (3.39), bTFE (3.33) and T2-TSE (3.56) performed equally without statistical difference. Visibility of venous pathologies was found to be equal between REACT (3.62), bTFE (3.51) and T2-TSE (3.52). The image degradation due to artifacts was rated best in T2-TSE (3.56), followed by REACT (3.39) and bTFE (3.33). CONCLUSIONS: REACT is a promising tool for the visualization of the pelvic venous system using magnetic resonance imaging.

Signal changes in T2-weighted MRI of liver metastases under bevacizumab-A practical imaging biomarker?

OBJECTIVE: The purpose of this study was to investigate signal changes in T2-weighted magnetic resonance imaging of liver metastases under treatment with and without bevacizumab-containing chemotherapy and to compare these signal changes to tumor contrast enhancement. MATERIALS AND METHODS: Retrospective analysis of 44 patients, aged 36-84 years, who underwent liver magnetic resonance imaging including T2-weighted and dynamic contrast enhancement sequences. Patients received bevacizumab-containing (n = 22) or conventional cytotoxic chemotherapy (n = 22). Magnetic resonance imaging was obtained at baseline and at three follow-ups (on average 3, 6 and 9 months after initial treatment). Three independent readers rated the T2 signal intensity and the relative contrast enhancement of the metastases on a 5-point scale. RESULTS: T2 signal intensity of metastases treated with bevacizumab showed a significant (p<0.001) decrease in T2 signal intensity after initial treatment and exhibit compared to conventionally treated metastases significantly (p<0.001 for each follow-up) hypointense (bevacizumab: 0.70 ± 0.83 before vs. -1.55 ± 0.61, -1.91 ± 0.62, and -1.97 ± 0.52; cytotoxic: 0.73 ± 0.79 before vs. -0.69 ± 0.81, -0.71 ± 0.68, and -0.75 ± 0.65 after 3, 6, and 9 months, respectively). T2 signal intensity was strongly correlated with tumor contrast enhancement (r = 0.71; p<0.001). Intra-observer agreement for T2-signal intensity was substantial (κ = 0.75). The agreement for tumoral contrast enhancement between the readers was considerably lower (κ = 0.39). CONCLUSION: Liver metastases exhibit considerably hypointense in T2-weighted imaging after treatment with bevacizumab, in contrast to conventionally treated liver metastases. Therefore, T2-weighted imaging seems to reflect the effect of bevacizumab.

FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers.

PURPOSE: FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398. EXPERIMENTAL DESIGN: FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors. RESULTS: Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398. CONCLUSIONS: FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.

Expression and role of the embryonic protein SOX2 in head and neck squamous cell carcinoma.

Recently, SOX2 has been identified as a potential lineage-specific oncogene in lung squamous cell carcinomas. Since head and neck squamous cell carcinomas (HNSCC) are morphologically and clinically highly related to lung squamous cell carcinomas, we hypothesized that SOX2 also plays an oncogenic role in this tumor entity. We assembled a cohort of 496 patients with HNSCC, including 253 metastases and 135 recurrences. SOX2 amplification (FISH) and SOX2 protein expression (immunohistochemistry) were correlated with molecular and clinicopathological parameters. In order to investigate the functional role of SOX2 in human HNSCC, SOX2 knockdown and overexpression in SCC-25 cells were generated by lentiviral constructs and subjected to cell cycle analysis, proliferation and apoptosis assays. Furthermore, SOX2 expression was correlated with the expression of proliferation and apoptosis-related proteins in primary HNSCC samples. SOX2 amplification was detected in 21% of primary HNSCC and mostly observed in a concordant manner between primary tumors and corresponding metastatic tissues. Overall, SOX2 amplification resulted in protein overexpression and was mutually exclusive with human papillomavirus infection. SOX2 protein overexpression was associated with clinicopathological parameters of worse outcome. Functionally, SOX2 induced the expression of the antiapoptotic protein BCL-2 and enhanced resistance to apoptosis-inducing agents including cisplatin, indicating SOX2 as a mediator of therapy resistance in human HNSCC. Targeting SOX2 and related molecular downstream pathways such as BCL-2 may enhance therapy efficacy in SOX2-expressing HNSCC.

Fibroblast growth factor receptor-1 as a potential therapeutic target in sinonasal cancer.

BACKGROUND: Despite multimodal treatment, sinonasal malignancies have an unfavorable prognosis. The purpose of this study was to elucidate if these tumors harbor amplifications of the fibroblast growth factor receptor 1 (FGFR1) gene, which has recently been identified as a potential therapeutic target in squamous cell lung cancer. METHODS: One hundred twelve primary tumors (including squamous cell carcinoma [SCC], carcinoma associated with an inverted papilloma, sinonasal undifferentiated carcinoma [SNUC], adenocarcinoma, adenoid cystic carcinoma [ACC], esthesioneuroblastoma, and 9 corresponding lymph node metastases) were assessed by fluorescence in situ hybridization (FISH) for FGFR1 copy number status. Human papillomavirus (HPV) status was assessed by p16 immunohistochemical as a surrogate marker. RESULTS: FGFR1 amplification was found in subsets of sinonasal SCCs (20%), carcinomas associated with an inverted papilloma (33%), and SNUCs (5%). In all cases, metastatic tumor samples shared the same FGFR1 amplification status as the corresponding primary tumor tissue. None of the FGFR1-amplified tumors expressed p16. CONCLUSION: FGFR1 amplification represents a potential molecular target in a subset of patients with sinonasal cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1253-1257, 2014.

Fibroblast growth factor receptor 1 amplification is a common event in squamous cell carcinoma of the head and neck.

Recently, we characterized fibroblast growth factor receptor 1 amplification as a target for a rational therapy in lung squamous cell carcinoma. Patients harboring this genetic event are currently eligible for treatment with antifibroblast growth factor receptor small-molecule inhibitors in phase I clinical trials. This has the potential to significantly improve standard therapy for lung squamous cell carcinoma patients. The aim of this study was to elucidate whether fibroblast growth factor receptor 1 amplification is also a common genetic event in head and neck squamous cell carcinoma. For this purpose, we assembled a cohort of 555 patients, including 264 with metastatic disease and 147 with recurrent disease. Formalin-fixed, paraffin-embedded material of primary tumors, metastases and recurrences were assessed for fibroblast growth factor receptor 1 copy number status using fluorescence in situ hybridization. Human papilloma virus status was detected by p16 immunohistochemistry staining and PCR-ELISA. Molecular parameters were correlated with each other and with clinicopathological data. We found 15% of primary head and neck squamous cell carcinoma to display a fibroblast growth factor receptor 1 amplification. In nearly all cases, metastatic and recurrent tumor samples shared the same amplification status as the corresponding primary tumor. Fibroblast growth factor receptor 1 amplification was associated with nicotine and alcohol consumption, but was mutually exclusive with human papilloma virus infection. Amplification of the gene was associated with parameters of worse outcome. Our data identify fibroblast growth factor receptor 1 amplification as a frequent event in primary and metastatic head and neck squamous cell carcinoma and represents a potential biomarker for more aggressive disease. Fibroblast growth factor receptor 1-amplified tumors could potentially comprise a subset of head and neck squamous cell carcinoma against which targeted small-molecule inhibitors hold therapeutic efficacy.

Sex determining region Y-box 2 (SOX2) amplification is an independent indicator of disease recurrence in sinonasal cancer.

OBJECTIVES: The transcription factor SOX2 (3q26.3-q27) is an embryonic stem cell factor contributing to the induction of pluripotency in terminally differentiated somatic cells. Recently, amplification of the SOX2 gene locus has been described in squamous cell carcinoma (SCC) of different organ sites. Aim of this study was to investigate amplification and expression status of SOX2 in sinonasal carcinomas and to correlate the results with clinico-pathological data. MATERIALS AND METHODS: A total of 119 primary tumor samples from the sinonasal region were assessed by fluorescence in-situ hybridization and immunohistochemistry for SOX2 gene amplification and protein expression, respectively. Of these, 59 were SSCs, 18 sinonasal undifferentiated carcinomas (SNUC), 10 carcinomas associated with an inverted papilloma (INVC), 19 adenocarcinomas (AD) and 13 adenoid cystic carcinomas (ACC). RESULTS: SOX2 amplifications were found in subsets of SCCs (37.5%), SNUCs (35.3%), INVCs (37.5%) and ADs (8.3%) but not in ACCs. SOX2 amplification resulted in increased protein expression. Patients with SOX2-amplified sinonasal carcinomas showed a significantly higher rate of tumor recurrences than SOX2 non-amplified tumors. CONCLUSION: This is the first study assessing SOX2 amplification and expression in a large cohort of sinonasal carcinomas. As opposed to AD and ACC, SOX2 amplifications were detected in more than 1/3 of all SCCs, SNUCs and INVCs. We therefore suggest that SNUCs are molecularly closely related to SCCs and INVCs and that these entities represent a subgroup of sinonasal carcinomas relying on SOX2 acquisition during oncogenesis. SOX2 amplification appears to identify sinonasal carcinomas that are more likely to relapse after primary therapy, suggesting that these patients might benefit from a more aggressive therapy regime.