Occult Primary (Carcinoma of Unknown Primary - CUP) in Head & Neck

DEFINITION

1. True CUP - primary never becomes clinically evident (possibly due to immune-mediated regression).
2. Occult primary - a small primary is present but undetected; the metastatic node outgrows the primary, which may later emerge if untreated.

HISTORICAL BACKGROUND

• In 1882, Volkmann believed the neck mass arose from degeneration of a branchiogenic cyst into carcinoma.
• In 1940, Martin challenged this, establishing criteria to distinguish true branchial cyst carcinoma from CUP.
• The second hypothesis for "true" CUPs: the primary tumour is eliminated by the innate/adaptive immune system before it becomes clinically manifest, but not before early metastasis to cervical nodes has occurred.

INCIDENCE

• In the 1970-80s, before universal cross-sectional imaging: 10-30% of HNSCC.
• With standardized diagnostic protocols, now reduced to ~5% of HNSCC cases.
• The most common presentation of CUP today is in the context of HPV-associated oropharyngeal SCC (HPV+OPSCC), as these tend to present with regional disease and a clinically unrecognized primary focus.
• As HPV+OPSCC numbers are rising, the raw incidence of CUP may also be increasing.

NOMENCLATURE (TNM - AJCC 8th Edition)

• T0 category is no longer assigned to p16-negative OPSCC and other non-HR HPV cancers (larynx, oral cavity, hypopharynx) because an exact primary site cannot be established.
• If FNAC of an enlarged cervical node confirms HPV positivity → primary site is determined to be oropharynx, allowing staging as HPV+ T0 OPSCC.
• If FNAC confirms EBV positivity → primary site is determined to be nasopharynx.
• This molecular staging allows more accurate treatment planning.

SITES AT RISK OF HARBOURING THE PRIMARY

1. Oropharynx - tonsil (most common), base of tongue (BOT)
2. Nasopharynx
3. Hypopharynx - pyriform sinus
4. Supraglottic larynx - infrahyoid epiglottis

• Level I nodes - almost never associated with nasopharyngeal primaries
• Level II/III - oropharynx, nasopharynx, larynx, hypopharynx
• Level V nodes - never associated with laryngeal cancer; suggest nasopharynx

EVALUATION AND DIAGNOSIS

Step 1: History and Clinical Examination

• Heavy smoking + alcohol - suggests primary outside nasopharynx (oral cavity, hypopharynx, larynx)
• Multiple sexual partners / orogenital contact - suggests HPV-related oropharyngeal primary
• Thorough examination including flexible fibre-optic nasolaryngoscopy (FNL) - special attention to base of tongue, nasopharynx, infrahyoid epiglottis, pyriform sinuses

Step 2: FNAC of the Neck Node

• Ultrasound-guided FNAC of suspicious neck nodes (based on size and morphology) - confirms metastatic SCC.
• HPV testing on FNAC material: HPV positivity strongly indicates an oropharyngeal primary (tonsil or BOT).
• EBV (EBER) testing: positivity suggests nasopharyngeal primary.

Step 3: Imaging

• Cross-sectional imaging (CT or MRI) of head and neck - first investigation at most centres.
• CT/PET-CT of thorax and upper abdomen - to exclude:
  • Synchronous primary bronchogenic carcinoma (linked aetiology with smoking)
  • Pulmonary and/or hepatic distant metastases

Step 4: FDG PET-CT (Key Investigation)

1. Detects unexpected primary site - sensitivity 84-89%, specificity 73-84%. Detects 31.4% more primary sites not found at conventional assessment (meta-analysis, 8 studies, 430 patients).
2. Detects unexpected nodal and distant metastases (contralateral neck, mediastinal, liver).
3. Detects occult synchronous cancers - especially silent lung and colorectal cancers.

Step 5: Narrow Band Imaging (NBI)

• NBI endoscopy (415 nm and 540 nm wavelength filters) highlights submucosal capillaries and abnormal mucosal vasculature, allowing identification of subtle mucosal lesions invisible on white-light endoscopy.
• NICE recommends using NBI in-clinic or under GA when PET-CT has failed to identify a primary site.

Step 6: Examination Under Anaesthesia (EUA) + Panendoscopy

• Bilateral tonsillectomy (ipsilateral tonsillectomy mandatory; bilateral preferred)
• Tongue base mucosectomy (TBM) - formal or targeted biopsy of BOT mucosa
• Biopsy of nasopharynx mucosa
• Biopsy of ipsilateral piriform fossa
• Transoral Robotic Surgery (TORS) robotic tongue base mucosectomy is increasingly used - allows systematic resection of lymphoid tissue of the BOT where small primary foci can hide.

A negative PET-CT does not preclude the need for panendoscopy and multiple biopsies.

CLINICAL MANAGEMENT

ENT-UK Multidisciplinary Treatment Guidelines (2016)

A. Early Disease (T0N1, no extracapsular spread)

• Single-modality therapy is adequate:
  • Neck dissection alone, OR
  • Radiotherapy alone (for small N1, high surgical risk patients)
• Some authors advocate neck dissection + watch-and-wait for the putative primary sites in N1 disease.

B. Advanced Disease (ECS, N2, N3)

• Combined modality therapy required:
  • Neck dissection (MRND/RND) + external beam radiotherapy (EBRT), ± chemotherapy.
  • Chemoradiotherapy (CRT) as primary treatment is an alternative to upfront surgery.

C. Surgical Management of the Neck

• Traditional approach: Neck dissection (MRND or RND) upfront, followed by RT or CRT.
  • Advantages: pathological staging of the neck; non-irradiated field; tailored adjuvant treatment.
  • Disadvantage: treatment delay if surgical complications occur.
• Selective neck dissection (SND - levels II-IV): Valid option for N2a/N2b disease; levels I and V rarely involved in CUP unless N3.
• Primary CRT: Reduces need for but may complicate subsequent surgery.
• Recent RCT evidence (from known primary setting): PET-CT-guided surveillance after radical CRT shows similar survival to upfront ND + CRT, with fewer NDs and fewer complications.

D. Radiation Fields - Ongoing Controversy

• Unilateral EBRT to neck + ipsilateral likely primary mucosal sites.
• Bilateral "Total Mucosal Irradiation" (TMI): Bilateral neck + all at-risk mucosal sites.
  • Bilateral EBRT shows improved local control rates and disease-free survival.
  • At the expense of increased xerostomia, dysphagia, feeding tube dependence.
• IMRT (Intensity-Modulated Radiotherapy): Current standard of care.
  • Allows parotid sparing, significantly reducing morbidity while maintaining disease control.
  • Now preferred for CUP patients receiving bilateral neck irradiation.

E. Management of the "Violated Neck"

• Some patients may have undergone prior open/incisional/excisional biopsy before diagnosis was established.
• Earlier reports suggested poor prognosis; current evidence shows no significant difference in prognosis if adequate and timely definitive treatment is given.
• Management options: upfront surgery (formal neck dissection) OR CRT followed by PET-CT surveillance and surgery as needed.

F. Branchial Cyst vs CUP

• All patients >35 years presenting with a lateral cystic neck mass should be presumed to have cancer until proven otherwise.
• These patients should enter a CUP investigation protocol even if FNAC is not diagnostic of metastatic SCC.

TREATMENT OUTCOMES

• Overall survival is generally good for both early and late-stage CUP.
• Recurrence pattern:
  • Recurrence typically occurs in the neck and as distant metastasis.
  • Distant metastases most commonly in the lung, usually within 1 year of treatment completion.
  • Emergence of primary tumour (if treatment fields inadequate) occurs mainly within first 24 months, usually in the oral cavity, oropharynx, or nasopharynx.
  • Recurrence at putative primary sites: 0-66%, mainly in surgery-alone patients.
• FDG PET-CT is the best method for detecting recurrence.
• Whether less intensive/single-modality therapy is adequate for HPV-positive CUP patients remains under investigation.

CONCLUSION

1. Structured diagnostic workup: FNAC + HPV/EBV testing → cross-sectional imaging → FDG PET-CT (before biopsy) → NBI → panendoscopy + bilateral tonsillectomy + TBM.
2. Treatment based on nodal stage (T0Nx) and MDT decision.
3. Single modality for early (N1 no ECS); combined modality for advanced disease.
4. IMRT is the current standard for radiation, reducing morbidity.
5. Molecular analysis (HPV, EBV) enables primary site assignment and guides staging under AJCC 8th edition.