Diagnostic Value of Preoperative uPAR-PET/CT in Regional Lymph Node Staging of Oral and Oropharyngeal Squamous Cell Carcinoma: A Prospective Phase II Trial.

The detection of lymph node metastases is a major challenge in oral and oropharyngeal squamous cell carcinoma (OSCC and OPSCC). 68Ga-NOTA-AE105 is a novel positron emission tomography (PET) radioligand with high affinity to urokinase-type plasminogen activator receptor (uPAR), a receptor expressed on the surfaces of tumor cells. The aim of this study was to investigate the diagnostic value of uPAR-PET/CT (computerized tomography) in detecting regional metastatic disease in patients with OSCC and OPSCC compared to the current imaging work-up. In this phase II trial, patients with OSCC and OPSCC referred for surgical treatment were prospectively enrolled. Before surgery, 68Ga-NOTA-AE105 uPAR-PET/CT was conducted, and SUVmax values were obtained from the primary tumor and the suspected lymph nodes. Histology results from lymph nodes were used as the standard of truth of metastatic disease. The diagnostic values of 68Ga-uPAR-PET/CT were compared to conventional routine preoperative imaging results (CT and/or MRI). The uPAR expression in resected primary tumors and metastases was determined by immunohistochemistry and quantified digitally (H-score). A total of 61 patients underwent uPAR-PET/CT. Of the 25 patients with histologically verified lymph node metastases, uPAR-PET/CT correctly identified regional metastatic disease in 14 patients, with a median lymph node metastasis size of 14 mm (range 3-27 mm). A significant correlation was found between SUVmax and the product of the H-score and tumor depth (r = 0.67; p = 0.003). The sensitivity and specificity of uPAR-PET/CT in detecting regional metastatic disease were 56% and 100%, respectively. When added to CT/MRI, uPAR-PET was able to upstage 2/11 (18%) of patients with occult metastases and increase the sensitivity to 64%. The sensitivity and specificity of 68Ga-NOTA-AE105 uPAR-PET/CT were equivalent to those of CT/MRI. The significant correlation between SUVmax and uPAR expression verified the target specificity of 68Ga-NOTA-AE105. Despite the target specificity, the sensitivity of imaging is too low for nodal staging and it cannot replace neck dissection.

Urokinase-Type Plasminogen Activator Receptor (uPAR) Expression and [64Cu]Cu-DOTA-AE105 uPAR-PET/CT in Patient-Derived Xenograft Models of Oral Squamous Cell Carcinoma.

PURPOSE: [64Cu]Cu-DOTA-AE105 urokinase-type plasminogen activator receptor (uPAR)-PET/CT is a novel and promising imaging modality for cancer visualization, although it has not been tested in head and neck cancer patients nor in preclinical models that closely resemble these heterogenous tumors, i.e., patient-derived xenograft (PDX) models. The aim of the present study was to establish and validate oral squamous cell carcinoma (OSCC) PDX models and to evaluate [64Cu]Cu-uPAR-PET/CT for tumor imaging in these models. PROCEDURES: PDX flank tumor models were established by engrafting tumor tissue from three patients with locally advanced OSCC into immunodeficient mice. [64Cu]Cu-DOTA-AE105 was injected in passage 2 (P2) mice, and [64Cu]Cu-uPAR-PET/CT was performed 1 h and 24 h after injection. After the last PET scan, all animals were euthanized, and tumors dissected for autoradiography and immunohistochemical (IHC) staining. RESULTS: Three PDX models were established, and all of them showed histological stability and unchanged heterogenicity, uPAR expression, and Ki67 expression through passages. A significant correlation between uPAR expression and tumor growth was found. All tumors of all models (n=29) showed tumor uptake of [64Cu]Cu-DOTA-AE105. There was a clear visual concordance between the distribution of uPAR expression (IHC) and [64Cu]Cu-DOTA-AE105 uptake pattern in tumor tissue (autoradiography). No significant correlation was found between IHC (H-score) and PET-signal (SUVmax) (r=0.34; p=0.07). CONCLUSIONS: OSCC PDX models in early passages histologically mimic donor tumors and could serve as a valuable platform for the development of uPAR-targeted imaging and therapeutic modalities. Furthermore, [64Cu]Cu-uPAR-PET/CT showed target- and tumor-specific uptake in OSCC PDX models demonstrating the diagnostic potential of this modality for OSCC patients.

Potential of uPAR, αvß6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry.

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets in head and neck cancer. We investigated the expression of nine imaging targets in both primary tumor and matched metastatic tissue of 41 patients with oral squamous cell carcinoma (OSCC) to assess their potential as targets for molecular imaging. The intensity, proportion, and homogeneity in the tumor and the reaction in neighboring non-cancerous tissue was scored. The intensity and proportion were multiplied to obtain a total immunohistochemical (IHC) score ranging from 0-12. The mean intensity in the tumor tissue and normal epithelium were compared. The expression rate was high for the urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvß6 (97%), and tissue factor (86%) with a median total immunostaining score (interquartile range) for primary tumors of 6 (6-9), 12 (12-12), and 6 (2.5-7.5), respectively. For the uPAR and tissue factor, the mean staining intensity score was significantly higher in tumors compared to normal epithelium. The uPAR, integrin αvß6, and tissue factor are promising imaging targets for OSCC primary tumors, lymph node metastases, and recurrences.

No difference in disease-free survival after oral cancer resection with close tumor margins in patients with and without postoperative radiotherapy.

We conducted a retrospective follow-up study to determine if adjunctive radiotherapy (RT) affected disease-free survival in patients with oral squamous cell carcinoma (SCC) who were found to have close surgical margins after tumor resection. Our study population was made up of 110 patients-72 men and 38 women, aged 30 to 94 years (median: 66) at the time of diagnosis. Their follow-up ranged from 12 days to 5.2 years (median: 3.6 yr). Of this group, 40 patients had free margins, 55 patients had close margins, and 15 had involved margins after surgery. Only 31 of these patients received postoperative RT, including 17 who had close margins. We would expect to find better postoperative local tumor control with combined surgery and RT, but we found no statistically significant difference in disease-free survival between the surgery-plus-RT group and the surgery-only group (p = 0.72). We also found no significant difference in disease-free survival between patients with a tumor of the floor of mouth and those with a tumor of the tongue (p = 0.34). In the study population as a whole, the disease-free survival rate was 81.0% and the overall survival rate was 78.2%. Our findings support the trend toward a watch-and-wait approach before initiating postoperative RT for patients with close surgical margins. The decision should be carefully discussed between the surgeon, the oncologic radiotherapist, and the patient.

Improved survival of head and neck cancer patients in Greenland.

Previously, head and neck cancer (HNC) patients in Greenland have had significant diagnostic delay and poor survival rates. From 2005-2009 several initiatives have been made to ensure faster diagnosis and better survival. The aim of this study was to compare the prognosis before and after these initiatives were introduced. All Greenlandic patients diagnosed with HNC between 2005 and 2012 were included. Data were retrieved from medical records and national databases and compared with the period 1994-2003. A total of 98 patients were identified. Diagnostic delay was significantly lower compared to the period 1994-2004 (p=0.048). The 3-year overall survival was 56% for all HNC and 47% for nasopharyngeal carcinomas. We found that patients with HNC between 1994 and 2003 had a higher risk of death from all reasons compared with the period 2005-2012 (HR 2.17; CI 1.46-3.23) after adjustments for stage and diagnostic delay. Patients with head HNC in Greenland from 2005-2012 were diagnosed earlier and had a better overall survival compared to the period 1994-2003. The change in survival is more likely to be due to improvement in treatment rather than the initiated interventions. Although survival has improved in Greenland, demographic problems and lack of specialists remain a challenge.

Primary mucosal melanoma of the head and neck in Denmark, 1982-2012: Demographic and clinical aspects. A retrospective DAHANCA study.

Background The study was performed to determine the epidemiological, clinical, and histopathological characteristics and prognosis of primary mucosal melanoma of the head and neck (MMHN) in Denmark. Material and methods This was a national retrospective multicenter study of patients diagnosed with MMHN between 1982 and 2012 in Denmark. Data were retrieved from national databases and patient records. Incidence trends were examined for the entire period. We prepared survival curves and performed univariate and multivariate analysis for the period 1992-2012 to identify possible prognostic factors. Results No significant trends in incidence were found in the study period. The three-year overall and disease-free survival rates for MMHN were 46.5% and 35.5%, respectively. Negative margins was an independent predictor of disease-free survival, and age below 65, absence of distant metastases, and low overall TNM stage were predictors of overall survival. Radiotherapy did not improve survival significantly. Recurrence rates were high, even for patients with negative margins. Conclusions MMHN remains a rare disease with a poor prognosis, particularly for patients aged over 65, those with distant metastasis, and those with advanced TNM stage. Importantly, the rate of recurrence is lowest in patients with negative margins.

Risk factors for and consequences of inadequate surgical margins in oral squamous cell carcinoma.

OBJECTIVE: The purpose of this study was to examine which factors are associated with inadequate surgical margins and to assess the postoperative consequences. STUDY DESIGN: A retrospective cohort of 110 patients with oral squamous cell carcinoma treated with surgery during a 2-year period was examined. Clinical, histopathologic, and operative variables were related to the surgical margin status. Furthermore postoperative treatment data were compared with margin status. RESULTS: Univariate statistically significant associations were found between the tumor site in the floor of mouth, more advanced T-stage, increasing tumor thickness, and inadequate margins. Of the patients with involved margins, 87% were treated with postoperative radiotherapy or re-resection, but among patients with close margins, only 35% received either radiotherapy or re-resection. CONCLUSIONS: Clinical and histopathologic factors were associated with the inadequate margin. Postoperative treatment for patients with close margins is controversial, and more studies are needed to define clear guidelines.