Blog

• Overview:
  • The nasopharynx is the uppermost part of the pharynx:
    • A cuboidal muscular-mucosal space behind the nasal cavity and above the soft palate, anterior to the atlas (C1) and axis (C2)
  • It functions purely as a respiratory conduit:
    • Communicating anteriorly with the nasal cavity via the choanae and laterally with the middle ear via the Eustachian (pharyngotympanic) tubes
• Boundaries (walls)
  • Anterior:
    • Paired choanae (posterior nasal openings)
    • Bony margin bounded:
      • Anteroinferiorly by the horizontal plate of the palatine bone
      • Superiorly by the sphenoid body and vaginal process of the medial pterygoid plate
      • Laterally by the medial pterygoid plates
  • Roof and posterior wall:
    • Continuous, sloping surface formed by the sphenoid body and basilar (clival) occipital bone superiorly, continuing over the anterior arches of C1 and C2:
      • Mucosa adherent to the pharyngobasilar fascia
  • Lateral walls:
    • Organized around the Eustachian tube orifice
  • Floor / inferior boundary:
    • Open inferiorly, communicating with the oropharynx via the pharyngeal isthmus:
      • Upper surface of the soft palate forms the effective floor, and the isthmus closes during swallowing to prevent nasal reflux:
        • The nasopharyngeal cavity opens into the cavity of the oropharynx through the pharyngeal isthmus, which lies between the posterior border of the soft palate and the posterior pharyngeal wall:
          • This region is marked on the posterior pharyngeal wall by a fold of mucosa formed by the palatopharyngeal sphincter between the palatopharyngeus muscle and the superior pharyngeal constrictor muscle:
            • During swallowing, elevation of the soft palate and constriction of the palatopharyngeal sphincter seals off the pharyngeal isthmus, separating the nasopharynx from the oropharynx:
              • This prevents the retrograde flow of materials into the nasopharynx and nasal cavity
• Lateral wall structures:
  • Torus tubarius:
    • Prominent posterior lip of the tubal orifice:
      • Elevated by tubal cartilage
  • Salpingopalatine fold:
    • Anterior lip of the orifice
  • Torus levatorius:
    • Inferior elevation overlying the levator veli palatini
  • Salpingopharyngeal fold:
    • Mucosal fold below the torus tubarius overlying salpingopharyngeus
  • Fossa of Rosenmüller (pharyngeal recess):
    • Deep lateral mucosal depression behind the torus tubarius:
      • Its apex points toward the internal carotid artery:
        • With the foramen lacerum above:
          • Most common site of origin of nasopharyngeal carcinoma and a key surgical landmark
• Musculature:
  • Tensor veli palatini:
    • Opens the Eustachian during swallowing.
  • Levator veli palatini:
    • Elevates the soft palate:
      • Forms the torus levatorius
  • Salpingopharyngeus:
    • Runs in the salpingopharyngeal fold:
      • Mucosal fold below the torus tubarius
  • Superior constrictor:
    • Forms the muscular posterolateral wall
  • Pharyngobasilar fascia:
    • Suspends the pharynx from the skull base.
• Lymphoid tissue
  • Prominent components of Waldeyer’s ring:
    • Nasopharynx-associated lymphoid tissue
  • The nasopharyngeal tonsil (adenoids):
    • Lies on the roof / posterior wall:
      • Is prominent in children and atrophies with age:
        • Hypertrophy can obstruct nasal breathing or the Eustachian tube orifice
  • Tubal tonsils sit near the tubal orifices
• Epithelium
  • Largely respiratory (ciliated pseudostratified columnar) epithelium:
    • With areas of stratified squamous epithelium at contact / friction sites
• Neurovascular and clinical relations
  • Sensory innervation:
    • Trigeminal (V2, pharyngeal branch) and glossopharyngeal nerves
  • Deep lateral-wall structures:
    • Parapharyngeal internal carotid artery (lateral to the fossa of Rosenmüller)
    • Foramen lacerum and clivus posteriorly
    • Foramen ovale (V3) and pterygopalatine fossa contents (vidian nerve, sphenopalatine ganglion
    • V2 laterally / anteriorly:
      • These explain pathways of local spread and perineural invasion in nasopharyngeal carcinoma
• References
  • Endoscopic endonasal transpterygoid nasopharyngectomy: Anatomical considerations and technical note. Liu J, Zhao J, Wang Y, et al. Head & Neck. 2024;46(2):306-320. doi:10.1002/hed.27581.
  • Anatomy and assessment of the pediatric airway. Adewale L. Paediatric Anaesthesia. 2009;19 Suppl 1:1-8. doi:10.1111/j.1460-9592.2009.03012.x.

• RTOG-0129:
  • Was a phase 3 randomized trial (enrolled 2002 to 2005) conducted by the Radiation Therapy Oncology Group:
    • That tested whether accelerated-fractionation radiotherapy improves outcomes over standard-fractionation radiotherapy:
      • When each is given concurrently with cisplatin in locally advanced (stage III to IV) head and neck squamous-cell carcinoma
  • Its primary comparison was negative :
    • The two radiotherapy schedules produced equivalent survival:
    • But its retrospective HPV analysis became a landmark:
      • Establishing tumor HPV status as a strong independent prognostic factor in oropharyngeal cancer
• Design:
  • Population:
    • Patients with locally advanced (stage III to IV) squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx:
      • 743 randomized:
        • 738 analyzed
  • Standard-fractionation arm:
    • 70 Gy in 2 Gy fractions once daily, 5 days / week over 7 weeks (35 fractions), with cisplatin 100 mg/m² on days 1, 22, and 43 (3 cycles)
  • Accelerated-fractionation arm (concomitant boost):
    • 72 Gy over 6 weeks — 1.8 Gy / fraction to the large field, plus a second daily 1.5 Gy boost fraction during the last 12 treatment days — with cisplatin 100 mg/m² on days 1 and 22 (2 cycles)
  • Technique:
    • IMRT was not permitted:
      • Treatment used 2D / 3D conformal radiotherapy
  • Median follow-up was 4.8 years in the original report, with long-term follow-up of 7.9 years in later analyses
• Primary result (fractionation):
  • There was no significant difference between arms
  • The 3-year overall survival was 70.3% with accelerated fractionation versus 64.3% with standard fractionation (P=0.18; HR for death 0.90, 95% CI 0.72–1.13), and rates of high-grade acute and late toxicity were similar
  • This supported the conclusion that accelerated fractionation offers no efficacy advantage over conventional fractionation when combined with concurrent cisplatin
• Landmark HPV finding:
  • Among patients with oropharyngeal cancer, 63.8% (206/323) had HPV-positive tumors
  • These patients were younger, more often white, had fewer pack-years, and smaller primaries:
    • 3-year overall survival:
      • 82.4% (HPV-positive) vs 57.1% (HPV-negative); P<0.001
      • After adjustment for age, race, tumor / nodal stage, tobacco, and treatment:
        • HPV-positive status conferred a 58% reduction in risk of death (HR 0.42, 95% CI 0.27–0.66)
      • The 8-year overall survival rate was 70.9% vs 30.2% (HR 0.30, 95% CI 0.21–0.42)
• References:
  • Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010.
  • Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010.
  • Lacas B, Bourhis J, Overgaard J, et al. Role of Radiotherapy Fractionation in Head and Neck Cancers (MARCH): An Updated Meta-Analysis. Lancet Oncol. 2017.
  • De Felice F, Bonomo P, Sanguineti G, Orlandi E. Moderately accelerated intensity-modulated radiation therapy using simultaneous integrated boost: Practical reasons or evidence-based choice? A critical appraisal of literature. Head Neck. 2020.
  • Driessen CM, Janssens GO, van der Graaf WT, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck. 2016.
  • National Comprehensive Cancer Network. Head and Neck Cancers. 2026.
    Chow LQM. Head and Neck Cancer. N Engl J Med. 2020.
  • Budach V, Tinhofer I. Novel Prognostic Clinical Factors and Biomarkers for Outcome Prediction in Head and Neck Cancer: A Systematic Review. Lancet Oncol. 2019.

• Overview:
  • Nasopharyngeal carcinoma (NPC):
    • Typically presents with a painless upper-neck mass plus nasal, aural, and cranial nerve symptoms:
      • Reflecting the tumor’s origin in the fossa of Rosenmüller with lateral (parapharyngeal) and superior (skull base) spread
  • Early symptoms are non-specific:
    • So most patients present at advanced stage (III to IV)
• Presenting features by mechanism:
  • Neck mass (regional nodal spread):
    • Most common presentation (~75%):
      • Painless enlarged upper cervical node:
        • Often the first / only sign
    • Retropharyngeal and level II nodes:
      • Are first echelons
    • May occur without a visible primary
  • Nasal symptoms (primary tumor):
    • Epistaxis or blood-tinged discharge
    • Unilateral nasal obstruction
    • Rhinorrhea (nasal dysfunction ~73%)
    • “Nasal twang” or voice change with large tumors
  • Aural / eustachian tube dysfunction:
    • Unilateral serous otitis media
    • Conductive hearing loss
    • Tinnitus
    • Aural fullness (~62%):
      • The feeling of pressure, clogging, or fullness inside the ear:
        • Often described as having water or air trapped inside
  • Skull-base / cranial nerve involvement:
    • Headache (~35%)
    • Facial pain / numbness (CN V)
    • Diplopia (~11%, CN VI)
    • Cranial nerve palsy in ~20% of the cases at diagnosis
    • Most affected nerves:
      • CN V and VI, plus III and XII
      • Advanced disease may cause cavernous sinus syndrome and multiple cranial neuropathies
  • Less common findings:
    • Trismus (~3%, pterygoid muscle invasion)
    • Nasal regurgitation (soft-palate paresis)
    • Symptoms of distant metastasis:
      • Bone, lung, liver
    • Anorexia / weight loss uncommon:
      • If present, raise suspicion for distant spread
• Evaluation:
  • Complete head and neck exam with nasopharyngeal fiberoptic endoscopy; neck palpation
  • EBV testing:
    • Endemic undifferentiated / nonkeratinizing subtypes strongly EBV-associated
  • Biopsy of nasopharyngeal lesion
  • MRI skull base to clavicle
• References:
  • Wei WI, Sham JS. Nasopharyngeal Carcinoma. Lancet. 2005.
  • Chua MLK, Wee JTS, Hui EP, Chan ATC. Nasopharyngeal Carcinoma. Lancet. 2016.
  • Ayan I, Kaytan E, Ayan N. Childhood Nasopharyngeal Carcinoma: From Biology to Treatment. Lancet Oncol. 2003.
  • Expert Panel on Neurological Imaging, Gule-Monroe MK, Calle S, et al. ACR Appropriateness Criteria® Staging and Post-Therapy Assessment of Head and Neck Cancer. J Am Coll Radiol. 2023.
  • Kumari B, Goyal MK, Lal V. Pearls & Oy-Sters: Bilateral Cavernous Sinus Syndrome as Presenting Manifestation of Nasopharyngeal Carcinoma. Neurology. 2014.
  • Brennan B. Nasopharyngeal Carcinoma. Orphanet J Rare Dis. 2006.
  • Her C. Nasopharyngeal Cancer and the Southeast Asian Patient. Am Fam Physician. 2001.
  • Albilali A, Alotaibi NH, Alfadley A, Alqarni KM, Alhajlah A. Extensive Locally Invasive Nasopharyngeal Carcinoma Involving 10 Cranial Nerves Palsies: An Interesting Case Report. Front Oncol. 2024.
  • Kumari B, Goyal MK, Lal V. Pearls & Oy-Sters: Bilateral Cavernous Sinus Syndrome as Presenting Manifestation of Nasopharyngeal Carcinoma. Neurology. 2014.
  • Kumari B, Goyal MK, Lal V. Pearls & Oy-Sters: Bilateral Cavernous Sinus Syndrome as Presenting Manifestation of Nasopharyngeal Carcinoma. Neurology. 2014.
  • Zhou P, Zhu Y, Xu B, et al. Cavernous Sinus Syndrome in a Patient With Occult Nasopharyngeal Carcinoma: A Diagnostic Challenge. Oral Oncol. 2025.
  • National Comprehensive Cancer Network. Head and Neck Cancers. 2026.
  • Chad Zender. Nasopharynx. Essential Cases in Head and Neck Oncology. 2022.
    
    
    

• History, Physical Exam, and Endoscopy
  • Complete H&P including full head and neck exam, with mirror examination as clinically indicated:
    • Nasopharyngeal fiberoptic examination
  • Documentation of tobacco (pack-years) and alcohol use with cessation counseling:
    • Distress screening
• Tissue Diagnosis
  • Biopsy of primary site or FNA of the neck:
    • Image-guided (US or CT) needle biopsy of cystic neck nodes may improve yield over palpation-guided FNA
  • Core biopsy preferred when systemic therapy is planned for unresectable / metastatic disease:
    • Allows biomarker testing
• Imaging of Primary and Neck
  • MRI with and without contrast from skull base to clavicle, ± CT skull base/neck with contrast
    • MRI preferred for:
      • Skull base invasion, cranial nerve involvement, perineural spread, intracranial / orbital extension, marrow invasion
    • CT complementary for cortical bone erosion / destruction
• Imaging for Distant Metastases
  • FDG-PET / CT and / or chest CT with contrast:
    • Bone scan if PET / CT not done
  • FDG-PET/CT preferred for locoregionally advanced disease (T3 to T4 or ≥ N1)
  • Dedicated contrast-enhanced brain MRI:
    • Reserved for histologies where brain metastasis is a concern
• Virology and Biomarkers
  • EBV / DNA testing:
    • For nonkeratinizing or undifferentiated histology:
      • Test tumor tissue and blood
  • Tissue:
    • ISH for EBV-encoded RNA (EBER) or IHC for latent membrane protein (LMP)
  • Blood:
    • Plasma / serum EBV DNA load by PCR (BamHI-W, EBNA, or LMP targets):
      • Reflects prognosis and treatment response
  • Consider HPV testing (may inform etiology)
• Additional Evaluations as Clinically Indicated
  • Dental / prosthodontic evaluation
  • Nutrition, speech, and swallowing evaluation/therapy
  • Audiogram
  • Consideration of ophthalmologic and endocrine evaluation
  • Fertility / reproductive counseling
  • Screening for hepatitis B
  • Multidisciplinary consultation
• Staging
  • Clinical staging follows AJCC / UICC TNM (9th ed.):
    • Distinct from other head and neck subsites:
      • Nodal criteria use a 6-cm size cutoff and the caudal border of the cricoid cartilage as a landmark
      • T0 defined by EBV-positive cervical nodes without identifiable primary
    • Workup culminates in classification into M0 vs M1 pathway
• Key Practical Points
  • Endoscopy plus biopsy is the diagnostic gold standard:
    • Most tumors arise in the fossa of Rosenmüller:
      • Targeted / blind biopsies appropriate:
        • When no tumor is visible but suspicion is high
  • MRI is the preferred modality for local staging:
    • Reported 100% sensitivity, 84% specificity in one series
  • FDG-PET / CT is the most sensitive test for nodal and distant metastasis
  • Plasma EBV DNA is more sensitive / specific than serum IgA / VCA titers:
    • Correlates with stage, and normalizes with successful treatment:
      • Useful for baseline risk stratification and post-treatment monitoring
  • WHO histology:
    • Keratinizing SCC
    • Nonkeratinizing carcinoma:
      • Differentiated
      • Undifferentiated:
        • Lymphoepithelioma-like carcinoma is a variant of the undifferentiated type
    • Basaloid SCC
  • In non-endemic regions:
    • A larger fraction of NPC is EBV-negative:
      • More often keratinizing / HPV-associated):
        • Lowering EBV DNA diagnostic yield
• References
  • Head and Neck Cancers. National Comprehensive Cancer Network. Updated 2026-05-12.
  • ACR Appropriateness criteria® for nasopharyngeal carcinoma. Saba NF, Salama JK, Beitler JJ, et al. Head & Neck. 2016;38(7):979-86. doi:10.1002/hed.24423.
  • Nasopharyngeal Carcinoma. Chua MLK, Wee JTS, Hui EP, Chan ATC. Lancet (London, England). 2016;387(10022):1012-1024. doi:10.1016/S0140-6736(15)00055-0.
  • The Role of Cross-Sectional Imaging in Suspected Nasopharyngeal Carcinoma. Shayah A, Wickstone L, Kershaw E, Agada F. Annals of the Royal College of Surgeons of England. 2019;101(5):325-327. doi:10.1308/rcsann.2019.0025.
  • Nasopharyngeal Carcinoma. Chen YP, Chan ATC, Le QT, et al. Lancet (London, England). 2019;394(10192):64-80. doi:10.1016/S0140-6736(19)30956-0.
  • Comparison of Plasma Epstein-Barr Virus (EBV) DNA Levels and Serum EBV Immunoglobulin a/Virus Capsid Antigen Antibody Titers in Patients With Nasopharyngeal Carcinoma. Shao JY, Li YH, Gao HY, et al. Cancer. 2004;100(6):1162-70. doi:10.1002/cncr.20099.
  • Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma: A Brief Review. Xue F, He X. Methods in Molecular Biology (Clifton, N.J.). 2020;2204:99-107. doi:10.1007/978-1-0716-0904-0_9.
  • Circulating Tumor DNA in Head and Neck Cancer. Kansara S, Contrera K, Roof S, et al. JAMA Otolaryngology– Head & Neck Surgery. 2026;:2851926. doi:10.1001/jamaoto.2026.2045.

• The paraglottic space (PGS):
  • Is a bilateral, deep fascial compartment of the larynx:
    • Filled with fat and loose connective tissue
  • Definition:
    • The paraglottic space (PGS) is a fat- and muscle-containing connective tissue compartment of the larynx:
      • Whose greatest clinical importance is:
        • As a preferential pathway for the spread of laryngeal cancers:
          • Particularly transglottic tumors
      • As a prognostic and surgical planning determinant
    • It surrounds the laryngeal ventricle:
      • Lies deep to the true and false cords:
        • Between the mucosa and inner surface of the thyroid cartilage:
          • It communicates directly with the preepiglottic space:
            • Allowing tumor to move rapidly between compartments 
    • It spans the supraglottic, glottic, and subglottic regions:
      • Playing a critical role in clinical oncology:
        • Because it acts as a primary, hidden pathway for the “transglottic” spread of laryngeal cancers
• Anatomical Boundaries
  • It was first described by:
    • Tucker and Smith in 1962
  • The paraglottic space is a tetrahedral-shaped compartment bounded by several cartilaginous and fibroelastic structures:
    • Anterolaterally: 
      • The inner surface of the thyroid cartilage
    • Superomedially: 
      • The quadrangular membrane:
        • Which separates it from the false vocal folds
      • The space is continuous with (or, in some specimens, separated by a collagenous septum from) the preepiglottic space
    • Inferomedially: 
      • The conus elasticus:
        • Which separates it from the subglottis
    • Posteriorly / Posterolaterally / Dorsally: 
      • The mucosal lining of the piriform sinus
    • Anteriorly: 
      • It communicates directly with the pre-epiglottic space
• Content of the Space:
  • The paraglottic space houses several vital neurovascular and muscular structures embedded within its protective layer of loose areolar and adipose tissue:
    • Adipose tissue: 
      • Abundant fat:
        • That makes the space highly visible on CT and MRI scans
    • Intrinsic laryngeal muscles: 
      • Including the thyroarytenoid, lateral cricoarytenoid, and posterior cricoarytenoid muscles
    • Blood vessels and nerves: 
      • Glands, blood vessels, and branches of the superior and inferior laryngeal nerves
• Clinical Significance:
  • The primary clinical importance of the paraglottic space:
    • Lies in laryngeal oncology and tumor staging:
      • Transglottic Spread: 
        • Because the PGS crosses the level of the laryngeal ventricle without physical barriers:
          • A squamous cell carcinoma originating in the true vocal cords can easily migrate vertically through this space into the false vocal cords (or vice versa):
            • This is known as transglottic spread
      • Cancer Staging: 
        • Invasion of the inferior paraglottic space can limit vocal fold mobility
        • In the TNM staging system, tumor invasion into the paraglottic space:
          • Automatically elevates a glottic or supraglottic laryngeal cancer to a T3 stage:
            • Altering the treatment trajectory from localized therapy to systemic options or extensive surgery
      • Surgical Planning: 
        • Knowledge of the paraglottic space borders is vital for performing voice-sparing, partial laryngectomies
        • If a tumor completely infiltrates this space:
          • A total laryngectomy may be required to ensure clean margins

• References:
  • Joo YH, Park JO, Cho KJ, Kim MS. Relationship between paraglottic space invasion and cervical lymph node metastasis in patients undergoing supracricoid partial laryngectomy. Head Neck. 2012.
  • Tamaki A, Miles BA, Lango M, Kowalski L, Zender CA. AHNS Series: Do you know your guidelines? Review of current knowledge on laryngeal cancer. Head Neck. 2018.
  • Reidenbach MM. The Paraglottic Space and Transglottic Cancer: Anatomical Considerations. Clin Anat. 1996.
  • Reidenbach MM. Borders and Topographic Relationships of the Paraglottic Space. Eur Arch Otorhinolaryngol. 1997.
  • Joo YH, Park JO, Cho KJ, Kim MS. Relationship between paraglottic space invasion and cervical lymph node metastasis in patients undergoing supracricoid partial laryngectomy. Head Neck. 2012.
  • Ferrari M, Schreiber A, Mattavelli D, et al. Surgical anatomy of the parapharyngeal space: Multiperspective, quantification-based study. Head Neck. 2019.
  • Wang XR, Wang H, Gao Y, et al. Study on the Ultrasonic Characteristics of the Paraglottic Space at the Glottic Level in Normal Adults. Head Neck. 2026.
  • Virós Porcuna D, Pollán Guisasola CM, Viña Soria C, et al. Transoral robotic parapharyngeal space dissection. Head Neck. 2024.
  • Mohamed A, Paleri V, George A. A cadaveric study quantifying the anatomical landmarks of the facial artery and its parapharyngeal branches for safe transoral surgery. Head Neck. 2019.
  • Hearn MW, Vogel CT, Laughlin RM, et al. Review of Spaces. Atlas of Operative Oral and Maxillofacial Surgery. 2022.
  • Dammann F, Wartenberg J. Diseases of the Head and Neck. Radiology-Nuclear Medicine Diagnostic Imaging. 2023.

• HPV Positive Oropharyngeal Squamous Cell Carcinoma (HPV⁺ OPSCC):
  • Radiation therapy (RT) + cetuximab vs RT + cisplatin (why substitution fails)
• Clinical rule: 
  • In cisplatin-eligible HPV⁺ oropharynx cancer:
    • Do not replace cisplatin with cetuximab:
      • To “de-intensify”
  • Two large phase III trials showed:
    • Worse survival and control with cetuximab
  • RTOG-1016 (Lancet 2019; non-inferiority trial):
    • Design: 
      • RT + cetuximab vs RT + cisplatin 100 mg / m² × 2 in HPV⁺ OPSCC
      • Primary endpoint OS:
        • Non-Inferiority (NI) margin HR 1.45
    • Results (median f/u ~ 4.5 y):
      • 5-yr OS: 
        • 77.9% cetuximab vs 84.6% cisplatin:
          • HR 1.45 → non-inferior criterion failed:
            • Inferior with cetuximab
      • PFS: 
        • HR 1.72:
          • Worse with cetuximab
      • Locoregional failure: 
        • HR 2.05:
          • Higher with cetuximab
      • Acute / late grade ≥ 3 toxicity: 
        • Overall similar rates (different profiles):
          • So efficacy — not toxicity — drives the choice PubMed+1
  • De-ESCALaTE HPV (Lancet 2019; “low-risk” HPV⁺):
    • Design: 
      • RT + cetuximab vs RT + cisplatin
      • Primary end point:
        • Severe toxicity
    • Efficacy (≈ 2 y):
      • OS: 
        • 97.5% cisplatin vs 89.4% cetuximab:
          • HR ~ 5.0:
            • Significantly worse with cetuximab
      • Recurrence: 
        • 6.0% cisplatin vs 16.1% cetuximab:
          • HR ~ 3.4
      • Severe toxicity: 
        • Similar overall rates
        • More sever adverse effects (SAEs) with cisplatin:
          • But not enough to offset the clear efficacy loss with cetuximab The Lancet+2Taylor & Francis Online+2
  • Reinforcing data:
    • ARTSCAN III (mixed HNSCC, HPV- subset reported):
      • Concurrent cisplatin outperformed cetuximab with RT:
        • Mature results reiterate inferior outcomes with cetuximabPMC+1
    • Guidelines: 
      • NCCN and contemporary reviews state that RT + cisplatin remains standard for eligible HPV⁺ OPSCC:
        • Cetuximab – RT is reserved for:
          • True cisplatin ineligibility:
            • CrCl < 50 mL / min, grade ≥ 2 SNHL / neuropathy) JNCCN
• How to use this at tumor board:
  • Eligible for cisplatin?
    • RT + cisplatin:
      • q3-weekly 100 mg / m² × 2 to 3, or weekly in appropriate settings:
        • To achieve ≥ 200 mg/m² cumulative if feasible (De-escalation ≠ drug substitution) PubMed
    • Cisplatin-ineligible? 
      • RT + cetuximab (or institutionally accepted alternatives) with explicit counseling that efficacy:
        • Is inferior to cisplatin in HPV⁺ disease:
          • Use only because platinum cannot be given JNCCN

• Primary squamous cell carcinoma of the parotid gland (pSCCP):
  •  Is a rare, aggressive salivary gland malignancy diagnosed only by exclusion:
    • After metastatic / secondary spread from a cutaneous or mucosal head and neck SCC, high-grade mucoepidermoid carcinoma, salivary duct carcinoma with squamous differentiation, and direct extension have all been ruled out
  • It is a contested entity:
    • Contemporary genomic data show that nearly all “parotid SCCs” carry a UV-induced mutational signature indicating cutaneous origin:
      • So the great majority of cases coded as primary are in fact metastatic (mSCCP)
• Definition and the diagnosis-of-exclusion problem
  • True pSCCP is thought to arise from squamous metaplasia of excretory duct epithelium:
    • By convention requires no evidence of any other primary squamous source
• pSCCP and mSCCP are histologically nearly identical:
  • Every criterion proposed to favor a primary (e.g., ductal dysplasia) can also occur when metastatic tumor grows along preexisting ducts
• SCC differentiation can also be seen in genetically defined salivary carcinomas :
  • NUT carcinoma, high-grade mucoepidermoid carcinoma, basal-type salivary duct carcinoma:
    • Further narrowing the space for a “true” primary
• Epidemiology
  • SCC accounts for roughly 0.3% to 1.5% of salivary gland tumors in classic series:
    • Though registry data (which cannot distinguish primary from metastatic) label a much higher share:
      • Up to ~ 23% of parotid cancers in one German national study, and ~ 2% of parotid neoplasms at a single institution after strict histologic review
    • Registry-based incidence has risen (~ 0.87 to 2.0 per million in SEER over 42 years):
      • Paralleling rising cutaneous SCC incidence and an aging population:
        • Most likely reflecting misclassified metastatic disease
    • The German registry found:
      • SCC-type parotid cancer was strongly associated with a prior head and neck SCC (adjusted OR 5.48), median interval 365 days:
        • Supporting frequent secondary origin
  • Typical patient:
    • Elderly (7th decade)
    • Male predominance:
      • Roughly 2:1
    • Presentation is often advanced, with a parotid mass, facial nerve dysfunction, and / or cervical nodes:
      • The majority present at stage IV
• Pathohistology and immunohistochemistry:
  • Keratinizing to nonkeratinizing infiltrative squamous nests with intercellular bridges / keratinization:
    • Keratinization is seen in ~1 in 6 metastatic SCC cases and is rare in the main mimics
  • Squamous markers p40, p63, CK5/6 are positive:
    • Mucicarmine should be negative:
      • Positive mucin points to mucoepidermoid carcinoma
  • Androgen receptor (AR) and / or HER2 positivity:
    • Should raise salivary duct carcinoma with squamous differentiation rather than pSCCP:
      • AR / CK7 expression does not exclude SDC
  • FNA differential includes:
    • Warthin tumor (well-differentiated cases)
    • High-grade mucoepidermoid carcinoma
    • Salivary duct carcinoma
  • UV-signature mutational analysis:
    • Is now the most useful ancillary tool to establish cutaneous (metastatic) origin
• Work-up:
  • The NCCN Head and Neck Cancers guidelines outline evaluation of any parotid mass:
    • Complete H&P with full head and neck exam (including mirror / fiberoptic exam), FNA biopsy, and, as clinically indicated, contrast CT / MRI from skull base to clavicle, chest CT, dental / nutrition / speech evaluation, and multidisciplinary consultation
    • Because SCC histology mandates excluding a metastatic source:
      • Workup should additionally include a thorough cutaneous exam of the face / scalp / ear (cutaneous SCC is the most common tumor to metastasize to the parotid), and an occult-primary / mucosal SCC evaluation when no skin primary is found:
        • EUA, direct laryngoscopy, tonsillectomy, chest / abdomen / pelvis CT or FDG-PET/CT, with p16 / HPV and EBV testing
    • FNA:
      • Reliably distinguishes benign from malignant (sensitivity ~ 80%, specificity ~ 97%) and is highly accurate for high-grade cancers
• Staging:
  • Historically staged with the AJCC 8th edition (2017) TNM for major salivary glands
  • T category is size / extraparenchymal-extension based:
    • T1 ≤ 2 cm
    • T2 > 2 to 4 cm
    • T3 > 4 cm and / or extraparenchymal extension
    • T4a skin / mandible / ear canal / facial nerve
    • T4b skull base / pterygoid plates / carotid encasement)
    • An important caveat:
      • The newly published AJCC / UICC 9th edition (TNM9) creates a unified salivary-gland-specific system but explicitly excludes squamous cell carcinoma (along with neuroendocrine and basosquamous carcinoma) from salivary gland staging:
        • Practically, parotid SCC is therefore staged using the head and neck cutaneous / mucosal SCC or cervical-node / unknown-primary frameworks rather than the salivary-gland schema
• Management:
  • No prospective trials exist; management is extrapolated from salivary gland and cutaneous / metastatic SCC guidelines and retrospective series
  • The consistent message across data sets is that surgery is essential:
    • Outcomes without resection are poor
  • The core approach for resectable disease is:
    • Total (at least superficial) parotidectomy + neck dissection + adjuvant radiotherapy
  • Per NCCN for major salivary gland cancers:
    • Primary treatment:
      • Complete surgical resection, with neck dissection for high-grade and / or T3 to 4 tumors (or clinically N+ disease):
        • The facial nerve is preserved when feasible
    • Adjuvant therapy:
      • Adjuvant RT is preferred for adverse features:
        • High grade, close / positive margins, perineural / neural invasion, nodal metastases, lymphovascular invasion, or high-grade T3 to T4a tumors (SCC qualifies as high grade)
    • –Unresectable / gross residual disease: 
      • Definitive RT, or concurrent systemic therapy / RT (category 2B)
  • ASCO guidelines:
    • Recommend that for advanced (T3 to T4) or high-grade parotid cancers, at least a superficial parotidectomy with removal of additional at-risk parotid tissue be performed (given planned adjuvant RT):
      • Balancing oncologic clearance against facial nerve risk:
        • There are no data that more aggressive parotidectomy improves survival or locoregional control when adjuvant RT is used
• Prognosis:
  • Uniformly aggressive regardless of primary-vs-metastatic classification
  • Reported median survival is roughly 13 to 24 months, and 5-year overall survival does not exceed ~ 50%
  • Larger tumor size, extraparenchymal extension, nodal metastases, distant metastases, and advanced age independently predict worse survival
  • Recurrent disease carries a particularly poor prognosis (median ~14.5 months)
  • Secondary (metastatic) parotid SCC has worse survival than true primary salivary cancers and higher rates of facial nerve sacrifice
• References:
  • Primary Squamous Cell Carcinoma of the Parotid Gland: Study and Review of the Literature. Horáková Z, Stárek I, Kalfert D, et al. In Vivo (Athens, Greece). 2024 Jan-Feb;38(1):358-364. doi:10.21873/invivo.13446.
  • Metastatic Cutaneous Squamous Cell Carcinoma Accounts for Nearly All Squamous Cell Carcinomas of the Parotid Gland. Bradley PJ, Stenman G, Thompson LDR, et al. Virchows Archiv : An International Journal of Pathology. 2024;485(1):3-11. doi:10.1007/s00428-024-03798-5.
  • Squamous Carcinoma in a Major Salivary Gland: A Review of the Diagnostic Considerations. Taxy JB. Archives of Pathology & Laboratory Medicine. 2001;125(6):740-5. doi:10.5858/2001-125-0740-SCIAMS.
  • Histogenesis of Salivary Gland Neoplasms. Regezi JA, Batsakis JG. Otolaryngologic Clinics of North America. 1977;10(2):297-307.
  • Salivary duct carcinoma with squamous differentiation: histomorphological and immunophenotypical analysis of six cases. Dababneh MN, Griffith CC, Magliocca KR, Stojanov IJ. Histopathology. 2024;85(4):590-597. doi:10.1111/his.15217.
  • Squamous cell carcinoma of the parotid gland. Ying YL, Johnson JT, Myers EN. Head & Neck. 2006;28(7):626-32. doi:10.1002/hed.20360.
  • Squamous Cell Carcinoma of the Parotid Gland: A Population-Based Registry Study of Primary Versus Metastatic Disease. Oesterling F, Möller L, Kajüter H, et al. Cancer Epidemiology. 2026;102:103085. doi:10.1016/j.canep.2026.103085.
  • Primary Squamous Cell Carcinoma of the Parotid Gland: The Importance of Correct Histological Diagnosis. Flynn MB, Maguire S, Martinez S, Tesmer T. Annals of Surgical Oncology. 1999;6(8):768-70. doi:10.1007/s10434-999-0768-y.
  • Incidence and survival trends of parotid malignancies over 42 years. Gupta A, Koochakzadeh S, Neskey DM, Nguyen SA, Lentsch EJ. Head & Neck. 2020;42(9):2308-2315. doi:10.1002/hed.26172.
  • Prognostic factors for squamous cell cancer of the parotid gland: An analysis of 2104 patients. Chen MM, Roman SA, Sosa JA, Judson BL. Head & Neck. 2015;37(1):1-7. doi:10.1002/hed.23566.
  • The key radiologic and cytomorphologic features of oncocytic and oncocytoid lesions of the salivary gland. Lubin D, Song S, Zafar HM, Baloch Z. Diagnostic Cytopathology. 2019;47(6):617-636. doi:10.1002/dc.24175.
  • Head and Neck Cancers. National Comprehensive Cancer Network. Updated 2026-05-12.
  • Cutaneous squamous cell carcinoma of the head and neck metastasizing to the parotid gland—A review of current recommendations. O’Hara J, Ferlito A, Takes RP, et al. Head & Neck. 2011;33(12):1789-95. doi:10.1002/hed.21583.
  • Occult Primary (Cancer of Unknown Primary [CUP]). National Comprehensive Cancer Network. Updated 2026-05-04.
  • Management of Salivary Gland Malignancy: ASCO Guideline. Geiger JL, Ismaila N, Beadle B, et al. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. 2021;39(17):1909-1941. doi:10.1200/JCO.21.00449.
  • Key Updates on the Version 9 AJCC/UICC Staging System for Salivary Gland Carcinoma. Huang SH, Seethala RR, Patel SG, et al. Annals of Surgical Oncology. 2026;33(6):4958-4963. doi:10.1245/s10434-026-19350-5.
  • Proposed Version Nine of the AJCC and UICC TNM Classification for Salivary Gland Carcinoma. Huang SH, Cotler J, Palis B, et al. JAMA Otolaryngology– Head & Neck Surgery. 2026;152(4):366-375. doi:10.1001/jamaoto.2025.5396.
  • Primary Squamous Cell Carcinoma of the Parotid Gland: Clinicopathological Characteristics, Treatment, and Prognosis. Xiao M, Liu J, You Y, Yang X, Wang Y. International Journal of Oral and Maxillofacial Surgery. 2021;50(2):151-157. doi:10.1016/j.ijom.2020.06.010.
  • Primary and Secondary Tumors of the Parotid Gland: Clinical Features and Prognosis. Pecorari G, Pizzo C, Briguglio M, Cravero E, Riva G. Cancers. 2023;15(4):1293. doi:10.3390/cancers15041293.

• The pterygopalatine fossa:
  • Is a small, cone- or inverted pyramid-shaped depression located deep within the upper face
  • It sits beneath the apex of the orbit, posterior to the maxilla, and medial to the infratemporal fossa
  • It acts as a major neurovascular crossroad connecting multiple regions of the skull
• Borders / Boundaries – The borders of the pterygopalatine fossa are formed by the palatine, maxilla and sphenoid bones:
  • Anterior: 
    • Maxillary tuberosity and posterior surface of the maxilla
  • Posterior: 
    • Pterygoid process of the sphenoid bone (lateral pterygoid plate)
  • Medial: 
    • Perpendicular plate of the palatine bone
  • Lateral: 
    • Pterygomaxillary fissure opening into the infratemporal fossa
  • Superior: 
    • Inferior surface of the greater wing of the sphenoid bone
    • Inferior orbital fissure of the eye
  • Inferior:
    • Pyramidal process of the palatine bone
• Major Contents:
  • Maxillary nerve (V2): 
    • The second division of the trigeminal nerve (cranial nerve V):
      • Passing through via the foramen rotundum (middle cranial fossa)
  • Pterygopalatine ganglion (Sphenopalatine ganglion): 
    • A parasympathetic ganglion:
      • Associated with cranial nerve VII
  • Maxillary artery: 
    • The third (terminal) part of the maxillary artery and its accompanying branches
  • Nerve of the pterygoid canal (Vidian nerve): 
    • Carrying sympathetic (via the deep petrosal nerve) and parasympathetic fibers (via the greater petrosal nerve) into the fossa
• Communications and Openings:
  • The fossa communicates with surrounding anatomic regions via several key foramina and fissures:
    • Middle cranial fossa: 
      • Via the foramen rotundum
    • Orbit: 
      • Via the inferior orbital fissure
    • Nasal cavity: 
      • Via the sphenopalatine foramen
    • Oral cavity / Palate: 
      • Via the greater and lesser palatine canals
    • Infratemporal fossa: 
      • Via the pterygomaxillary fissure
    • Pharynx / Nasopharynx: 
      • Via the pharyngeal / palatovaginal canal
• Clinical Significance:
  • Because of its numerous pathways and high density of nerves and blood vessels:
    • The pterygopalatine fossa can act as a conduit for the spread of infections and malignant tumors from the face or nasal cavity into the cranial vault
  • Surgeons also target this area for nerve blocks or approaches to control severe bleeding (epistaxis)

• Surgical margin status:
  • Remains one of the most powerful and actionable prognostic factors in oral tongue / oral cavity SCC
• Classically, Scholl and colleagues:
  • Reviewed 268 patients with squamous carcinoma of the oral tongue:
    • They found that 54 (20.1%) had microscopic “cut-through” at the intraoperative frozen section margin:
      • An initially positive margin
  • Even when additional resection converted these to final negative margins:
    • Local control remained significantly worse:
      • Than in patients whose margins were clear on the first pass
  • They also reported that margin involvement patterns differed by T stage:
    • T1 to T2 tumors:
      • More often had positive mucosal margins
    • T3 to T4 tumors:
      • Commonly failed at the deep / soft-tissue margins
• Similar observations were made in classic series evaluating “positive” epidermoid carcinoma margins in the head and neck:
  • Looser, Shah, and Strong:
    • Demonstrated that patients with involved margins:
      • Had substantially higher local recurrence than those with negative margins:
        • With early reports quoting local recurrence in roughly two-thirds to three-quarters of patients with positive margins versus about one-third with negative margins
  • Loree and Strong:
    • Subsequently examined 398 oral cavity SCCs:
      • Showing that positive or “close” margins (tumor at or within 0.5 mm of the inked edge, or significant premalignant change / in situ carcinoma at the margin):
        • Were associated with a doubling of local recurrence (36% vs 18%) and inferior 5-year survival compared with negative margins (52% vs 60%)
• The reliability and utility of intraoperative frozen section (FS) margin assessment have also been extensively studied:
  • Spiro et al:
    • Reported an overall intraoperative FS diagnostic accuracy of:
      • Roughly 89% for oral tongue cancer:
        • Importantly found that accuracy was similar whether sections were taken directly from the patient’s tumor bed or from the oriented surgical specimen
    • Positive or “close” margins:
      • Defined in their series as tumor present at the ink or within roughly one high-power field of the resection edge:
        • Were associated with a significantly increased risk of local recurrence (p < 0.003)
  • Subsequent work by Byers and others:
    • Confirmed the prognostic and therapeutic value of frozen section (FS):
      • Guided re-resection in HNSCC:
        • But also highlighted that FS cannot fully compensate for suboptimal initial resection planes
• Definitions of margin status and distance:
  • There is now better consensus on margin nomenclature
  • Most contemporary series and guidelines define:
    • Positive margin:
      • Invasive carcinoma or severe / high-grade dysplasia:
        • At the inked edge, or < 1 mm from the inked edge
    • Close margin:
      • Invasive carcinoma typically 1 to 4 or 1 to 5 mm from the inked edge:
        • Cut-off values vary:
        • But a 5 mm microscopic threshold is most commonly used in oral cavity SCC
    • Clear margin:
      • ≥ / > 5 mm from invasive tumor to the inked edge after formalin fixation
• Tasche et al., in a large JAMA Otolaryngology analysis:
  • Proposed that a distance < 1 mm behaves biologically like an involved margin:
    • With similarly high local recurrence risk
  • Whereas 1 to 5 mm margins had intermediate risk and ≥ 5 mm margins were associated with the lowest recurrence
• More recent multicenter work emphasizes the importance of deep margin distance in particular:
  • With data suggesting that deep margins ≤ 3 mm carry a significantly higher risk of local failure compared with > 3 mm:
    • Even when the mucosal margin is wide
• Impact of positive and close margins on outcomes:
  • Multiple retrospective series and meta-analyses now support and refine the early observations of Scholl, Looser, Loree, and Strong:
    • Positive final margins are consistently associated with:
      • ~ 2-fold higher risk of local recurrence,
        increased regional / distant failure in some series, and significantly worse disease-specific and overall survival
  • Binahmed et al. and McMahon et al:
    • Both showed that patients with involved margins:
      • Had roughly double the local recurrence and significantly poorer survival compared with those with clear margins, and that close margins behaved intermediately between clearly negative and frankly positive margins
  • Liao et al:
    • Identified margin status, together with T stage, DOI, and perineural invasion:
      • As major predictors of local tumor control in oral cavity SCC
  • A 2019 systematic review and meta-analysis by Gorphe:
    • Concluded that positive margins carry an approximately two-fold increased risk of death and local failure across head and neck sites, independent of other factors
  • More granular contemporary analyses, including Buchakjian et al. and Szewczyk et al., have shown that:
    • Positive margins (< 1 mm) remain the strongest margin-related predictor of:
      • Local, regional, and distant recurrence
    • Close margins (1 to 4.9 mm) often do not independently worsen outcomes if other adverse factors (lymphovascular invasion, perineural invasion, ENE, nodal disease, advanced T stage):
      • Are absent and if appropriate adjuvant therapy is given when indicated
  • The prognostic effect of close margins is modulated by:
    • Depth of invasion (DOI), pattern of invasion, and composite histologic risk models (e.g., Brandwein-Gensler)
  • Subsite-specific studies have further refined this:
    • Tongue and floor-of-mouth tumors are particularly prone to failure at the deep margin:
      • In several series, deep margin positivity or ≤ 2 to 3 mm clearance:
        • Has been more predictive of local recurrence than mucosal margin distance
• Microscopic cut-through and “revised” margins:
  • Building on Scholl’s original work, the concept of microscopic tumor cut-through (MTCT):
    • A positive FS margin that is revised to negative on final pathology, has been extensively studied
    • Patel et al. (Head & Neck 2010) showed that MTCT:
      • Was associated with significantly worse local control and disease-specific survival compared with margins that were negative from the outset:
        • Particularly in patients with nodal disease
    • Guillemaud et al. similarly reported that intraoperative cut-through, even if revised to R0:
      • Predicted higher local recurrence and worse outcomes in oral cavity SCC
    • A meta-analysis by Bulbul et al. concluded that clearance of a positive margin improves outcomes relative to leaving it unrevised:
      • But patients with MTCT still fare worse than those whose margins were always negative:
        • Suggesting MTCT is a marker of more aggressive biology and / or challenging local anatomy
    • More recently, Agne et al. evaluated T3 to T4 OCSCC and confirmed that MTCT:
    • Remained an independent predictor of local recurrence on multivariable analysis (HR ~1.8–2.2 for local failure):
      • Although its effect on disease-specific survival attenuated when controlling for nodal stage and other high-risk features
• These data support considering MTCT as a high-risk feature warranting discussion of treatment intensification:
  • For example (e.g., adjuvant chemoradiotherapy) in a multidisciplinary tumor board, even when final margins are technically negative
• Kwok et al. addressed the related question of “clear versus revised margins” in 417 patients with oral and pharyngeal carcinoma:
  • Patients who required immediate re-resection for a positive FS margin but ended with R0 status:
    • Had survival similar to those with primary R0 resection, and both groups did substantially better than patients left with residual microscopic or macroscopic disease
  • This suggests that while MTCT carries biologic risk:
    • An aggressive intraoperative strategy to convert to R0 is still beneficial and should remain standard practice
• Intraoperative margin assessment:
  • Specimen vs tumor bed:
    • There is growing recognition that how margins are sampled:
      • Is almost as important as the final measurement
    • Meier et al.’s AHNS survey and several subsequent series have documented wide variation in intraoperative margin practices (tumor bed vs specimen mapping, number of samples, definition of “adequate” clearance), and a substantial rate of FS–permanent section discrepancy
  • Key contemporary points include:
    • Specimen-based mapping (oriented and inked, with communication between surgeon and pathologist):
      • Tends to provide more reliable correlation between FS and final margins than random tumor-bed biopsies
    • FS accuracy remains high (often ~ 85% to 95%):
      • But false-negatives and false-positives still occur:
        • Particularly at the deep margin, in previously irradiated fields, and in specimens with significant shrinkage
    • In some series, “complete FS margins” with a measurable 1 to 5 mm histologic buffer were associated with improved local control compared with conventional limited sampling
  • Recent reviews and consensus statements (e.g., Kubik et al., Kain et al., Chen et al. 2024) now recommend:
    • A planned 1 to 1.5 cm gross resection margin in vivo for oral tongue SCC, anticipating ~30% to 50% shrinkage with formalin fixation and tissue relaxation
    • Routine use of oriented, inked specimens with targeted FS from high-risk areas (deep margin, close relationship to muscle bundles or neurovascular structures)
    • Consideration of advanced adjuncts—near-infrared fluorescence mapping, specimen 3D-mapping, and emerging augmented-reality registration—for difficult tongue and floor-of-mouth resections
• Integration with histologic risk models:
  • Finally, margin status must be interpreted in the context of overall histologic risk
  • The Brandwein-Gensler model:
    • Worst pattern of invasion, perineural invasion, lymphocytic host response and later refinements:
      • Have shown that high-risk tumors have markedly increased recurrence and disease-specific mortality even when margins are clear
  • Conversely, some low-risk early-stage tumors with close (but not involved) margins may do well without aggressive adjuvant therapy
  • This supports a nuanced, risk-adapted approach in which:
    • Positive margins or MTCT → strong indication for adjuvant chemoradiotherapy in most patients
    • Close margins (1 to 4 mm) → individualized decision based on DOI, nodal status, PNI/LVI, pattern of invasion, and patient-specific factors
    • Clear margins (≥ 5 mm) → lowest risk group, managed according to other adverse features
• Reviewed:
  • Scholl P, Byers RM, Batsakis JG, Wolf P, Santini H. Microscopic cut-through of cancer in the surgical treatment of squamous carcinoma of the tongue: prognostic and therapeutic implications. Am J Surg. 1986;152:354-360. 
  • Looser KG, Shah JP, Strong EW. The significance of “positive” margins in surgically resected epidermoid carcinomas. Head Neck Surg. 1978;1:107-111. 
  • Loree TR, Strong EW. Significance of positive margins in oral cavity squamous carcinoma. Am J Surg. 1990;160:410-414. 
  • Spiro RH, Guillamondegui O, Paulino AF, et al. Pattern of invasion and margin assessment in patients with oral tongue cancer. Head Neck. 1999;21:408-413. 
  • Chen TY, Emrich LJ, Driscoll DL. The clinical significance of pathological findings in surgically resected margins of the primary tumor in head and neck carcinoma. Int J Radiat Oncol Biol Phys. 1987;13:833-837. 
  • McMahon J, O’Brien CJ, Pathak I, et al. Influence of condition of surgical margins on local recurrence and disease-specific survival in oral and oropharyngeal cancer. Br J Oral Maxillofac Surg. 2003;41:224-231. 
  • Binahmed A, Nason RW, Abdoh AA. The clinical significance of the positive surgical margin in oral cancer. Oral Oncol. 2007;43:780-784. 
  • Liao CT, Chang JTC, Wang HM, et al. Analysis of risk factors of predictive local tumor control in oral cavity cancer. Ann Surg Oncol. 2008;15:915-922. 
  • Patel RS, Goldstein DP, Guillemaud J, et al. Impact of positive frozen section microscopic tumor cut-through revised to negative on oral carcinoma control and survival rates. Head Neck. 2010;32:1444-1451. 
  • Guillemaud J, Patel RS, Goldstein DP, et al. Prognostic impact of intraoperative microscopic cut-through on frozen section in oral cavity squamous cell carcinoma. J Otolaryngol Head Neck Surg. 2010;39:370-377. 
  • Kwok P, Gleich O, Hübner G, Strutz J. Prognostic importance of “clear versus revised margins” in oral and pharyngeal cancer. Head Neck. 2010;32:1479-1484. 
  • Gorphe P. A systematic review and meta-analysis of margins in head and neck cancer. Oral Oncol. 2019;95:93-101. 
  • Tasche KK, Buchakjian MR, Pagedar NA, Sperry SM. Definition of “close margin” in oral cancer surgery and association of margin distance with local recurrence rate. JAMA Otolaryngol Head Neck Surg. 2017;143:1166-1172. 
  • Buchakjian MR, Tasche KK, Robinson RA, et al. Association of main specimen and tumor bed margin status with local recurrence and survival in oral cancer surgery. JAMA Otolaryngol Head Neck Surg. 2016;142:1191-1198. 
  • Kain JJ, Birkeland AC, Udayakumar N, et al. Surgical margins in oral cavity squamous cell carcinoma: current practices and future directions. Laryngoscope. 2020;130:128-138. 
    Szewczyk M, et al. A matter of margins in oral cancer—how close is enough? Cancers (Basel). 2024;16(8):1488. 
  • Agne GR, et al. Oncologic outcomes of microscopic tumor cut-through in locally advanced oral squamous cell carcinoma. Arch Head Neck Surg. 2022;51:e20220013. 
    Chen Y, et al. Surgical margins in head and neck squamous cell carcinoma. Int J Surg. 2024;109:54-66. 
  • Brandwein-Gensler M, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 2005;29:167-178.