Cancer of an unknown primary (CUP), or an occult primary, refers to the presence of metastatic lesions proven by histological examination when there is no known detectable site of the primary tumors by conventional methods1. Unfortunately, CUP of head and neck is one of the most common cancers worldwide. Unsuccessful detection of an occult primary leads to suboptimal treatment planning, thus negatively affecting patient prognosis1. 18F-FDG PET/CT, a non-invasive molecular imaging procedure, has proven to be a valuable procedure in the diagnosis of CUP. In addition, the association between Human papillomavirus (HPV) and primary tumors has been established. The purpose of this research is to explore the role of PET/CT in the evaluation of occult primary of the head and neck cancers analyzed by HPV status.
Keywords: PET/CT, occult primary, HPV.
PET/CT In Diagnosis of Occult Primary Of Head And Neck Cancers Analyzed by HPV status
Head and neck cancers are a major cause of morbidity and mortality around the world.2 In 2008, more than 500,000 cases were reported, with around 6,000 patients from the United Kingdom, making head and neck cancers the most fifth prevalent carcinomas.3 In addition, cancer of unknown primary (CUP) of the head and neck often metastasizes to the lymph nodes, accounting for approximately 3-5% of all head and neck malignant tumors.4 Schmalbach and Miller4 pointed out that identifying the sites of occult primary cancer is essential for allowing site-specific therapy and for minimizing the side effects of radiation from treatment. Thus, several diagnostic methods have been applied to the detection of primary lesions. These methods include physical assessment and endoscopy of the head, neck, and upper aerodigestive tract in addition to cross-sectional imaging with Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Although the majority of primary tumors are successfully detected by these investigations, 2-9% of the origins of primary tumors remain undiscovered.5
With advances in medical imaging technology,18F-fluorodeoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) has been widely utilized for staging, restaging, radiotherapy planning, and post-therapy follow-up in several head and neck cancers. According to Cammaroto et al.,2 PET/CT has been proven superior at identifying carcinoma of unknown primary, cervical lymph nodes adenopathy, and distal metastatic disease. It also offers and has advantages over CTs and MRIs in the detection of recurrent and second primary lesions.2 In a study of 78 patients who presented with neck nodal metastases with no primary cancer identified by CT/MRI, the authors found that PET/CT detected primary malignancies in 30 patients, with a recorded sensitivity and specificity of 100% and 66.7%, respectively, thus improving detection of occult primaries by 40%. 6 However, it remains unclear how often PET/CT is currently performed in routine clinical practice for occult primary.
Another imperative question is weather PET/CT should be performed as a first step in identifying occult primary or as a second procedure after CT/MRI imaging. In 2016, the National Institute for Health and Care Excellence (NICE)? recommended performing PET/CT as the first procedure to identify the primary site in patients presenting with metastatic nodal squamous cell carcinoma of unknown origin that is thought to arise from the upper aerodigestive tract.7 Nonetheless, a limited number of studies have evaluated the utility of a baseline PET/CT in the detection of occult primary of head and neck cancers.
Despite the advantages of PET/CT, Park et al.5 emphasized that small lesions might not be easily identified by 18F-FDG PET/CT, which may cause false-negative and false-positive scans.4 As a result, extensive research has been conducted to examine the association between various biomarkers, such as Human papillomavirus (HPV) and SCCUP, in order to identify the effects of positive or negative HPV status on the management of head and neck cancers. For instance, in a matched-pairs analysis conducted on 136 patients diagnosed of CUP, the results revealed a significant connection between HPV positive status and discovery of unknown lesions, which improved overall survival, cause-specific survival, and disease-free survival.8 In a retrospective study of 61 patients diagnosed with oropharyngeal squamous cell carcinoma (OSCC), the authors found that overall recurrence rates in positive and negative HPV patients were 24% and 55%, respectively. The results suggested that a negative first PET/CT post-therapy is associated with better prognostic value and less recurrence, particularly in patients affected by positive HPV infection.9 However, more research should be carried out to assess the effectiveness of PET/CT in identifying second primary/metastatic rates of head and neck carcinomas in patients affected by HPV.