Neck Cancer With Unknown Primary Site Workup

• Per anesthesia guidelines, routine labs (ECG, chemistries, CBC count, chest radiography) should be obtained in preparation for a panendoscopy and possible neck dissection in the operating room. Chemistries (eg, liver function tests [LFTs]) may also help to diagnose distant metastatic disease and to aid in the complete workup of staging the disease (TNM system).
• In addition to general lab studies, serology positive for Epstein-Barr virus has been shown to correlate with the presence of nasopharyngeal carcinoma.^{[11, 12]} However, the physical examination of the nasopharynx via endoscopy and directed biopsies of suspicious areas offers a higher yield.
• More recently, a study was published that attempted to determine the site of the primary tumors by identifying HPV-related carcinomas via fine needle aspiration, both morphologically and by using in situ hybridization (ISH), in metastatic cervical lymph nodes. Nonkeratinizing morphology or HPV-positivity were highly predictive of oropharyngeal origin of the tumor.^[13]

• Chest radiography (posteroanterior and lateral views)

  • This study allows the physician to screen for lung metastases from the occult primary malignancy or a concurrent primary lung neoplasm. Also, chest radiography helps in the complete staging of the disease process. If a suspicious lesion is found on chest radiograph, further investigation with a CT scan of the chest is warranted. Although no guidelines exist for screening for distant metastatic disease in advanced head and neck squamous cell carcinoma, recent studies had suggested that chest CTs were adequate screening tools for distant disease. Brouwer et al (2005) documented that the sensitivity and specificity was only 73% and 80%, respectively.^[14] His group suggests that FDG-PET scans may be a better alternative.
  • If the results are consistent with metastases, the lesion obviates the need for surgical intervention and makes the patient a possible candidate for radiation/chemotherapy.
  • If the findings on the CT scan are consistent with a primary lung neoplasm, this represents either a synchronous primary malignancy or a source of the cervical metastases.
  • If a primary lung neoplasm is discovered, the patient's care should be shared with the appropriate oncologist.
• CT scan of the head and neck with intravenous contrast

  • In terms of availability, cost effectiveness, quickness, and patient compliance, CT scanning is the imaging modality of choice for both the evaluation of cervical lymphadenopathy and the identification of occult primary lesions. Newer technology and methods of acquisition, such as the helical CT scanner, allows better image quality and resolution, better reconstructive capabilities, quicker scans, and decreased artifact. The quicker scans allow dynamic maneuvers to be used. The puffed cheek and modified Valsalva techniques can help open opposed mucosal surfaces in the oral cavity, oropharynx, and hypopharynx. This may allow the easier detection of unknown mucosal primaries.^[15] Nonetheless, critical evaluation of the CT scan helps in the location of directed biopsies during panendoscopy in the workup of the unknown primary tumor.^[3]
  • With respect to the evaluation of cervical lymphadenopathy, a CT scan of the neck is helpful in assessing the involvement of vital structures. It also provides the clinician with useful data regarding surgical resectability.
  • In addition to its usefulness in evaluating the clinically obvious neck mass, a CT scan, as seen in the image below, can be used to evaluate clinically negative cervical lymph node zones. Radiographic criteria of potential pathological lymph nodes include rounding of the lymph node, a size greater than 1.5 cm in the jugulodigastric region or greater than 1 cm in other regions, and a hypodense center of the lymph node that signifies necrosis. CT scan of neck with contrast. The arrows indicate metastatic lymphadenopathy. Image courtesy of Head and Neck Cancer-Multidisciplinary Approach, Davidson, BJ.
• MRI or magnetic resonance angiography of the head and neck

  • In the primary author's opinion, MRI is superior to CT scanning in anatomical detail and is helpful in iodine-allergic patients who need a contrast study. Unfortunately, MRI is slower than a CT acquisition and some patients may not be able to tolerate the physical constraints of the scanner.
  • MRI may be useful in the evaluation of the superior extent of metastatic cervical lymphadenopathy (ie, intracranial extension).
  • MRI may have a role in the preoperative workup of a patient with cancer of the head and neck once the primary site is known. The literature is limited in the use of current MRI technology (inversion recovery MRI, dynamic contrast enhanced MRI, MR spectroscopy, ultrasmall superparamagnetic iron oxide particles [USPIO], diffusion-weighted imaging) for the detection of the unknown primary; however, inversion recovery MRI has the best potential to identify the unknown primary. MRI is ideal for a patient with cancer on the base of the tongue or of the sinonasal tract.^[15]
  • Although angiography is the criterion standard for evaluating the integrity of the great vessels, magnetic resonance angiography (MRA) is a less-invasive procedure and can provide useful information. This information can be used in the determination of resectability.^[16]
• Positron emission tomography imaging with 2-fluoro-2-deoxyglucose

  • Positron emission tomography (PET) is not typically used in the workup of occult primary tumors of the head and neck. With a radio-labeled glucose molecule, this imaging modality works on the assumption that areas of high metabolism pick up the tracer. Cancer cells have a high standard uptake value (SUV); in addition, areas of inflammation and infection also show signs of high metabolism.
  • Historically, this imaging modality is most often used after the workup for an unknown primary cancer is complete but has not yet revealed the primary site. At the primary author's institution, the PET scan is often used in the initial workup of an unknown primary tumor to help guide biopsies during panendoscopy. One study claimed a sensitivity and specificity rate of 100% and 94%, respectively, for PET, compared with conventional methods rates of 92% and 76%, respectively.^[17] This is in contrast to a more recent study in which the PET sensitivity and specificity was 66% and 92.9%, respectively. The positive predictive and negative predictive values were 88.8% and 76.5%, respectively.^[18] Depending on the situation, the authors often fuse the PET scan with a CT scan, as seen in the image below, to further delineate the lesions. Theoretically, a fused PET/CT can visualize lesions larger than 5 mm. CT/positron emission tomography (PET) fusion; areas of uptake on the PET scan are mapped to the CT scan, and this image depicts the primary lesion in the left floor of mouth with metastatic disease to level II.
  • Because of the limited access to PET imaging and the controversy regarding the mixed evidence of PET imaging in the detection of unknown primary cancers, it is not part of a standard workup.^{[19, 20]} The use of fusing PET scans with CT scans for the workup of the unknown primary tumor is even further debated.^[21] However, more recent evidence suggests that the combination of PET and panendoscopy detected 45.2% of unknown primary tumors of the head and neck.^[18]

Fine-needle aspiration is the main diagnostic procedure in the workup of occult primary tumors of the head and neck. It is used to obtain a histological diagnosis of the presenting neck mass. The histology allows the clinician to narrow the differential diagnosis and to focus diagnostic and therapeutic treatment.