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.

• WHO Classification:
  • Keratinizing Squamous Cell Carcinoma (formerly WHO Type I):
    • Shows squamous differentiation with intercellular bridges and / or keratinization over most of its extent
    • More common in non-endemic areas:
      • Accounts for > 75% of NPC in the non-Asian US population (Caucasian)
    • Typically found in older adults:
      • Associated with smoking / alcohol
    • Carries the worst prognosis among the subtypes
    • Not typically associated with EBV:
      • HPV has emerged as a potential factor in this subtype
  • Non-Keratinizing Carcinoma (formerly WHO Types II and III):
    • The dominant subtype worldwide:
      • Constituting > 95% of cases in endemic regions:
        • Southern China
        • Southeast Asia
    • Strongly associated with:
      • EBV infection
    • More radiosensitive than the keratinizing subtype
    • Subdivided into:
      • Differentiated (formerly WHO Type II):
        • Cells show a maturation sequence without evident squamous differentiation on light microscopy
        • Fusiform or oval nuclei with scant cytoplasm
        • Display a stratified appearance and distinct cell margins
      • Undifferentiated (formerly WHO Type III):
        • Oval or round vesicular nuclei with prominent nucleoli, scant eosinophilic cytoplasma
        • Indistinct cell margins with a syncytial rather than pavemented appearance
        • Often called lymphoepithelioma (Schminke tumor) due to prominent admixed non-malignant lymphoid infiltrate
        • Most common subtype in endemic areas (~ 95% in southern China) and in children (~ 90%)
        • Basaloid Squamous Cell Carcinoma (added in 2005 WHO classification):
          • A rare subtype:
            • Also associated with EBV infection
          • Comprises a minimal subset of patients
• Evolution of the Classification:
  • The original 1978 WHO system:
    • Used a numerical scheme:
      • Types I, II, III
  • In 1991:
    • Types II and III were combined into a single “non-keratinizing carcinoma” category:
      • The numerical designations were dropped
  • The basaloid squamous cell carcinoma category:
    • Was added in the 2005 WHO classification
• Geographic Distribution of Subtypes:
  • North America:
    • ~25% type I, 12% type II, 63% type III
  • Southern China:
    • 2% type I, 3% type II, 95% type III
  • In the US:
    • Non-keratinizing subtypes:
      • Predominate in East / Southeast Asian populations
    • The discrepancy is explained by the racial /ethnic composition of the study populations:
      • In the US, disproportionately develop non-keratinizing (type III) NPC:
        • Which skews the overall North American numbers toward type III
      • When restricted to White / non-Asian patients, keratinizing SCC predominates
• References:
  • Chen YP, Chan ATC, Le QT, et al. Nasopharyngeal Carcinoma. Lancet. 2019.
  • KO, Mazul AL, Skillington SA, et al. The prognostic significance of race in nasopharyngeal carcinoma by histological subtype. Head Neck. 2021.
  • Alsavaf MB, Marquardt M, Abouammo MD, et al. Patient Characteristics and Treatment Outcomes of Nasopharyngeal Carcinoma in Nonendemic Regions. JAMA Netw Open. 2025.
  • Wei WI, Sham JS. Nasopharyngeal Carcinoma. Lancet. 2005.
  • Ayan I, Kaytan E, Ayan N.
    
    

• 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.

• NCCN Guidelines, Head and Neck Cancers (v2.2026) still base clinical staging definitions on AJCC 8th edition (ST-4 for p16-negative, ST-7 for p16-positive):
  • Version 9 is not yet incorporated
• Version 9 changes apply only to:
  • HPV-positive (p16+) oropharyngeal carcinoma
• The p16-negative oropharynx / hypopharynx system:
  • Is unchanged in the current NCCN tables
• T – Tumor:
  • TX – Primary tumor cannot be assessed
  • Tis – Carcinoma in situ
  • T1 – Tumor 2 cm or smaller in greatest dimension
  • T2 – Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
  • T3 – Tumor larger than 4 cm in greatest dimensión or extensión to lingual surface of epiglottis
  • T4 – Moderately advanced or very advanced local disease
    • T4a – Moderately advanced local disease
      • Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
    • T4b – Very advanced local disease
      • Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

• Lymph node metastases:
  • At presentation are common in OPSCC:
    • With over half of patients:
      • Having clinical or radiological evidence of cervical metastasis
    • Around a third of patients diagnosed as cN0:
      • Having pathologic evidence of lymph node metastasis
  • The lymphatic drainage from the oropharynx:
    • Is mainly to:
      • Levels II, III and IV
    • It also drains into:
      • The retropharyngeal (RP) nodes:
        • Which need to be considered in the assessment of disease in this area
        • The risk of metastasis to RP lymph nodes depends on subsite:
          • A meta-analysis of papers suggests risk of RP lymphadenopathy being:
            • 19% for soft palate
            • 12% for tonsil
            • 6% for base of tongue and
            • 21% to 57% for posterior pharyngeal wall tumors:
              • Including hypopharynx
      • The prognostic impact of positive RP lymph node metastasis is disputed:
        • Some authors showing an adverse impact:
          • And others not
  • A particular feature of OPSCC:
    • Is the propensity to metastasis to the contralateral neck:
      • This occurring in up to 30% of patients overall in one series:
        • The subsites in which this is mostly likely to occur are the:
          • Soft palate
          • Base of tongue
          • Posterior pharyngeal wall:
            • However:
              • Even tonsil cancers have an approximate rate:
                • Of contralateral nodal spread of 10%