Non‐FDG‐Avid Metastasis Detected by Molecular Imaging in Unknown Primary of the Head and Neck

ABSTRACT

Squamous cell carcinoma of unknown primary continues to be a diagnostic challenge. We present a case where a novel molecular imaging agent aided the identification of additional lesions missed on traditional imaging, ultimately leading to diagnosis and a change in management.

In a patient with squamous cell carcinoma of unknown primary, the use of molecular imaging identified an additional site of metastasis not seen on traditional PET/CT. This aided in proper diagnosis and alteration of the patient's treatment plan.

1. Introduction

Patients with cancer of unknown primary represent less than 5% of head and neck squamous cell carcinoma cases yet present a large diagnostic burden. 18‐F Fluorodeoxyglucose ([¹⁸F] FDG) positron emission tomography with computed tomography (PET/CT) is the most sensitive imaging technique used for detection of occult primary lesions; however, accurate detection within the head and neck ranges from 10% to 60% [1]. Improved imaging strategies are needed, and targeted molecular imaging is actively being investigated to aid in the diagnosis of unknown primary lesions. We present a case of a 64‐year‐old male who presented with head and neck squamous cell carcinoma (SCC) of unknown primary, whose final diagnosis and treatment plan was aided by the use of [⁸⁹Zr] panitumumab PET/CT. This prompted closer evaluation of the nasopharynx, which confirmed the primary site. This case is unique in that a novel imaging agent identified a site of metastasis not commonly seen in nasopharyngeal cancer that traditional imaging did not.

2. Case Report

A 62‐year‐old, white male with SCC of the right neck was referred to the otolaryngology head and neck surgical oncology clinic for further work up and management. His history was notable for previous tonsillectomy and adenoidectomy as a teenager and daily chewing tobacco use. He denied any cutaneous SCC history. Imaging included computed tomography (CT) and [¹⁸F] FDG PET/CT demonstrating the known cervical adenopathy measuring 3.7 × 2.3 × 3.4 cm within level 2 and an additional, deeper conglomerate measuring 2.4 × 2.4 × 2.6 cm within levels 3 and 5. There was no evidence of a primary on either scan. Outside institution core needle biopsy revealed poorly differentiated, p16 negative squamous cell carcinoma and a repeat fine needle aspiration in office confirmed these findings. Fine needle aspiration at our institution had insufficient cell block material for immunohistochemical studies. Physical examination including flexible laryngoscopy did not reveal a primary site.

The patient was enrolled in a clinical trial investigating [⁸⁹Zr] panitumumab PET/CT as a molecular imaging modality for identifying occult primary tumors in patients with head and neck SCC of unknown primary (NCT05747625). In addition to the already detected FDG‐avid lymph nodes, [⁸⁹Zr] panitumumab PET imaging revealed a right‐sided parotid lesion (SUV 2.3) that was not detected on the [¹⁸F] FDG scan (Figure 1). Additionally, the nasopharynx showed focal uptake of [⁸⁹Zr] panitumumab with an SUV of 3.0.

FIGURE 1.

PET images from the [¹⁸F] FDG and [⁸⁹Zr] panitumumab PET/CT scans which display the regions of interest. (A) Right parotid lymph node (B) Nasopharynx.

Ultrasound‐guided core needle biopsy of the parotid lesion identified on [⁸⁹Zr] panitumumab scan was performed for diagnosis and radiation planning, which revealed Epstein–Barr virus (EBV)‐associated SCC. The patient underwent intraoperative direct laryngoscopy with biopsy and nasal endoscopy with biopsy. Direct laryngoscopy with biopsy of the ipsilateral tonsil and base of tongue was negative. Nasal endoscopy revealed a small, sub‐centimeter area of granular mucosa. This was biopsied (Figure 2) and confirmed the diagnosis of EBV+ nasopharyngeal carcinoma (NPC).

FIGURE 2.

Nasopharyngeal Biopsy. Hematoxylin and eosin (H&E) stained section (A and B) from nasopharyngeal biopsy demonstrating poorly differentiated squamous cell carcinoma that was confirmed by EBV‐encoded RNA (EBER) staining (C and D).

3. Discussion

In this preliminary reporting of ongoing clinical trial outcomes, we demonstrate the potential utility of [⁸⁹Zr] panitumumab PET/CT as a novel molecular imaging modality in head and neck SCC. Imaging and physical exam failed to reveal a primary, and biopsies yielded insufficient material for complete viral testing [2]. Ultimately, the targeted scan prompted biopsy of the right parotid lesion for radiation contour planning, which showed an EBV+ SCC. This in combination with the increased activity in the nasopharynx on the [⁸⁹Zr] panitumumab PET/CT resulted in close examination of the nasopharynx and identification of a small, occult nasopharyngeal primary tumor. Biopsy of the nasopharynx showed EBV+ SCC, confirming the primary site.

Although the majority of NPC patients present with lymphadenopathy, the most common sites of metastasis are to the retropharyngeal and level II lymph nodes. Only around 1%–3% of cases are estimated to metastasize to the parotid in NPC [3].

Panitumumab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), which is overexpressed in SCC. It has previously been demonstrated that [⁸⁹Zr] panitumumab is highly specific to head and neck SCC, and combination with [¹⁸F] FDG results in improved specificity for detection of metastatic lymph nodes [4]. In this case, focal uptake of the nasopharynx and identification of a parotid lesion provided additional information to narrow down the primary site location. This fundamentally changed the treatment of this patient to include induction chemotherapy with gemcitabine and cisplatin [5], followed by more tailored radiotherapy with concurrent cisplatin.

4. Conclusion

In summary, this case demonstrates the added benefit of [⁸⁹Zr] panitumumab scan to [¹⁸F] FDG PET/CT in a patient with EBV+ NPC. Moving forward, we hope to continue optimizing this molecular imaging technique to further benefit patients with head and neck squamous cell carcinoma of unknown primary.

Ethics Statement

This study was reviewed and approved by Vanderbilt University Medical Center (VUMC) institutional review board. The patient provided informed consent, and all procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflicts of Interest

The authors declare no conflicts of interest.

Meeks N., McAdoo A., Lee J., et al., “Non‐FDG‐Avid Metastasis Detected by Molecular Imaging in Unknown Primary of the Head and Neck,” The Laryngoscope 135, no. 9 (2025): 3229–3231, 10.1002/lary.32228.