Validation of High-resolution PET/CT for the Pretherapeutic Lymphnode Staging of Head/Neck Cancer

In head and neck squamous cell carcinoma (HNSCC), the presence of lymph node metastases in addition to free resection margins following surgical resection of the primary tumor is an important prognostic factor, and may impact planning of surgery as well as of radiotherapy. Neck dissection and histopathology are regarded as diagnostic standard procedures to define the lymph node status in patients with HNSCC. Occult lymph node metastases after imaging have been described in up to 46% of patients, e.g. in patients with cancer of the tongue.

Although neck dissection generally has a low rate of intra- and postoperative complications, a small but statistically significant group of patients suffers from surgery-related side effects such as lymphedema, chronic pain syndromes and injury of cranial nerves with paralysis (shoulder lift and mouth angle). Therefore it would be desirable to spare diagnostic neck dissection in patients without macroscopic lymph node metastasis. However, the sensitivity and/or specificity of the non-invasive imaging techniques available up to now, including positron emission tomography (PET) and magnetic resonance imaging (MRI), did not allow to exclude lymph node metastases, which is especially true for small metastases. Therefore, imaging is not able to replace the histological examination of the cervical lymph nodes and have limited impact on the therapeutic concept, the surgical planning and the planning and dose prescription of radiotherapy.

Acquisition techniques and image quality of PET (with the glucose analog F-18-fluorodeoxyglucose (FDG)) and the combined examination with computed tomography (PET/CT) were considerably improved with last generation PET/CT machines. New generation PET/CT machines provide significantly improved image quality and image resolution image, and probably higher sensitivity to detect smaller lesions. However, in the face of an expected increase of detected metabolically active cervical lymph nodes by high-resolution (HR) PET/CT, a diagnostic problem in terms of a potentially increased number of false-positive lymph nodes arises, e. g. due to an inflammatory lymphadenopathy.

Until now there are no evidence-based criteria to classify small metabolically active lymph nodes detected by HR PET/CT. Hence, a correlation of PET/CT findings and histopathology of cervical lymph metastases and inflammatory lymph nodes in patients with HNSCC is required to develop diagnostic criteria for HR PET/CT and to exploit the diagnostic potential of HR PET/CT.

Modern concepts of radiotherapy planning for neck lymph node metastases increasingly take into consideration the metabolic and morphological information of PET/CT for target volume definition. Detailed information on the diagnostic performance of HR PET / CT are of importance for the dose prescription of intensity-modulated radiotherapy (IMRT). In radiotherapy side effects depend significantly on the dose and the irradiation volume. Modern radiation techniques, especially IMRT, allow for highly-conformal radiation therapy with steep dose gradients to protect organs such as the salivary glands, and to reduce side effects of radiotherapy. On the other hand modern radiotherapy concepts carry the risk to fail due to non-inclusion of subclinical lymph node metastases in the target volume. HR PET/CT may allow to minimize out-of-field recurrences caused by incorrect target volume contouring or dose prescription. Evidence-based data on the diagnostic accuracy of HR PET/CT with special regard to small lymph node metastases are needed to clarify the potential role of HR PET/CT for radiation treatment planning.

Objective:

• To determine the sensitivity, specificity, accuracy, PPV and NPV of lymph node staging with HR PET/CT in patients with HNSCC
• To determine the sensitivity, specificity, accuracy, PPV and NPV of HR PET/CT for lymph node metastases of different size in patients with HNSCC
• To determine the detection rate of distant metastases by PET/CT in patients with HNSCC
• To develop diagnostic criteria for the multi-modal lymph node staging with HR PET/CT in patients with HNSCC
• To evaluate the potential impact of HR PET/CT on radiation treatment planning

Methods:

Patients with HNSCC are managed according to clinical recommendations of the interdisciplinary tumor board. Elective patients receive selective, modified radical or radical neck dissection of the relevant lymph node region according to clinical routine standards at the Inselspital Bern. The neck dissection must be carried out within a maximum of 6 weeks after the PET / CT examination.

As part of the neck dissection the lymph nodes will be sent to the Institute of Pathology separated by level and side by topographic markers (cranial / caudal, medial / lateral). The histological examination of the removed lymph nodes serves as reference standard for the analysis of PET/CT image data, and calculation of the diagnostic accuracy of HR PET/CT.

Theoretical radiation treatment plans are generated based on conventional imaging, whole-body PET/CT and HR PET/CT protocols to determine the impact of PET/CT.

Inclusion criteria

• Head and neck squamous cell carcinoma (HNSCC), fulfilling one or more of the following criteria:

• Advanced primary tumor stage (cT3 or cT4)
• Clinical suspicion of neck lymph node metastases
• Cervical lymph node metastases of unknown primary tumor (CUP)
• Tumor recurrence
• Mature adult
• Written informed consent

Exclusion criteria

• Inoperability
• Histologically verified cervical lymph node metastases of other tumors