In the Chair: 3 Asymptomatic Patients, 3 Early-Stage Cancers

Head and neck squamous cell carcinoma has no established population-level screening program.¹ Most cases are diagnosed at advanced stages — and the survival difference between early and late-stage disease is stark: 70–90% at 5 years for early-stage, less than 20% for metastatic. The anatomy doesn’t help: tumors at the base of tongue, supraglottic larynx, and hypopharynx can remain invisible on routine exam without fiberoptic evaluation.

Multi-cancer early detection (MCED) tests — blood-based assays that analyze circulating cell-free DNA methylation patterns — are beginning to change that picture. Galleri (GRAIL), the most studied MCED assay, has among the highest sensitivity of any test for head and neck cancer, with Stage I sensitivity of 63% and Stage IV sensitivity of 96% in the CCGA validation study. As MCED testing enters primary care practice, APPs across specialties will increasingly encounter patients referred on the basis of a positive result. Knowing what to do — and how quickly — is no longer optional.²

This case series is from a head and neck surgery program, not dermatology. It appears here because MCED testing is entering dermatology practice through patients and through the skin cancer overlap with HPV-driven disease — and because APPs who understand the workup algorithm are better positioned to triage, counsel, and refer appropriately. Three clinical decision points follow, one per patient.

CLINICAL DECISION POINT 1—Patient A — 64-Year-Old Male, Positive MCED, 6-Month Delay

A 64-year-old man undergoes Galleri testing through his primary care provider. Results return indicating a cancer signal of head and neck and anal canal origin. He has coronary artery disease and carotid artery stenosis. A CT of the neck is obtained and shows bilateral tonsillar hypertrophy. The patient attributes this to a concurrent acute viral illness. He elects observation. Six months later, he presents to your clinic for evaluation of the still-unaddressed positive MCED result. On examination, you note fullness of the right tonsil with mucosal irregularity. NavDx (HPV-associated ctDNA assay) is obtained and returns positive.

⚠️CLINICAL CONTEXT

At the time of his positive MCED result, this patient had no symptoms he attributed to malignancy and a seemingly reassuring explanation for his imaging findings. The 6-month delay before otolaryngologic evaluation was not the recommended course of action.

📋WHAT WOULD YOU DO?

CLINICAL DECISION POINT 2—Patient B — 64-Year-Old Male, Normal Exam, Negative NavDx

A second 64-year-old man is referred to you following a Galleri result indicating an HPV-associated head and neck cancer signal. His review of systems is negative. On examination, his palatine tonsils appear completely normal, and there is no palpable cervical lymphadenopathy. Flexible laryngoscopy is within normal limits. CT of the neck demonstrates a prominent left level 2A lymph node. PET confirms a single hypermetabolic left level 2A cervical lymph node without an identifiable primary lesion anywhere in the pharynx or head and neck. NavDx testing is obtained and returns negative.

⚠️CLINICAL CLUE

Two out of 3 patients in this series had no clinical evidence of disease on thorough physical examination and laryngoscopy. A normal exam after a positive MCED result does not clear the patient. NavDx negativity in an HPV-associated signal does not exclude malignancy.

📋WHAT WOULD YOU DO?

CLINICAL DECISION POINT 3—Patient C — 49-Year-Old Male, Positive NavDx, Nondiagnostic FNA

A 49-year-old man is referred following a Galleri result indicating an HPV-associated head and neck cancer signal. He has no significant past medical history and his review of systems is otherwise unremarkable. On examination, you note a palpable, firm 2 cm left level 2 cervical lymph node with symmetric bilateral tonsillar enlargement and no mucosal ulceration. Flexible laryngoscopy demonstrates asymmetric left tonsillar fullness. PET confirms an asymmetrically enlarged, FDG-avid left palatine tonsil and a hypermetabolic left level 2A cervical lymph node suspicious for nodal metastasis. NavDx returns positive. Fine needle aspiration of the left cervical lymph node is performed and returns nondiagnostic.

📋WHAT WOULD YOU DO?

The table below summarizes the diagnostic workup, pathologic findings, and outcomes across the 3 patients in this series:

✓A positive MCED result with head and neck cancer signal origin requires urgent otolaryngology referral within 2–4 weeks — patient-attributed explanations for imaging findings do not override this

✓Physical exam and flexible laryngoscopy can be completely normal even in confirmed early-stage oropharyngeal SCC — a normal exam does not clear a positive MCED result

✓NavDx (HPV-specific ctDNA) is complementary to MCED testing, not confirmatory — a negative NavDx does not exclude malignancy and should not delay biopsy when imaging is suspicious

✓All confirmed MCED-identified HNSCC cases in the published literature to date are p16+ oropharyngeal SCC arising from the palatine tonsil, occurring in male patients at early stage

✓A nondiagnostic FNA in the setting of a convergent clinical picture (positive MCED, positive NavDx, FDG-avid imaging) should prompt surgical evaluation, not repeat sampling

✓Galleri demonstrates among the highest MCED sensitivity for any cancer type: Stage I sensitivity 63%, Stage IV 96%, with cancer signal of origin accuracy approximately 90%

THE TAKEAWAY

None of these 3 patients had symptoms. Two of them had normal physical examinations and normal laryngoscopy. All 3 had early-stage p16+ oropharyngeal squamous cell carcinoma. The only reason any of them received a diagnosis when they did was because a blood test flagged a cancer signal — and because their clinicians followed through on it.

MCED testing is entering primary care at scale. Patients will present to dermatology clinics, urgent care visits, and annual wellness exams with a printout showing a positive Galleri result and a head and neck cancer signal origin. The clinical question APPs will face is not whether to take it seriously — the data are clear that they should — but how to act on it: refer urgently, understand that a normal exam doesn’t clear the result, and know that NavDx negativity is not a green light to step back. The algorithm the authors propose is practical: urgent ENT referral, comprehensive exam with laryngoscopy, cross-sectional imaging, NavDx for HPV-associated signals, directed biopsy, p16 IHC and HPV ISH on oropharyngeal tissue, and multidisciplinary tumor board for confirmed diagnoses.

Head and neck cancer has no established screening program. MCED testing, imperfect as it is, may be the closest thing to one that exists right now. APPs who understand the workup are positioned to make a difference in the window where it matters most.

References

1. Dittmann P, Lehnert B, Ihler F, Busch CJ, Blaurock M. Structured early follow-up in head and neck squamous cell carcinomas: a retrospective cohort study. Biomedicines. 2025;13(5):1246. Published 2025 May 20. doi:10.3390/biomedicines13051246
2. Talwar A, Ben-Levy O, Sriram N, Samant S. The role of multicancer early detection tests in head and neck squamous cell carcinoma: a case series. Head Neck. Published online May 28, 2026. doi:10.1002/hed.70337