Radiation Oncology/Head & Neck/Nasopharynx/Overview

Nasopharyngeal Cancer Overview

Epidemiology

• Markedly different geographical prevalence
  • Rare in the US: 0.2-0.5 cases per 100,000 people
  • Common in China, Hong Kong and Taiwan: 25-50 per 100,000. Accounts for ~5% of all cancers and ~50% of H&N cancers in Taiwan
  • Also common in North Africa, the Middle East, and in Inuits
• Association with salted fish, Ebstein-Barr virus
• Smoking and alcohol don't have a clear association with the disease
• In general, affects a younger population
• Up to 90% present with N+ disease, and ~50% have bilateral N+ disease

Clinical Presentation

• Most commonly presents with a neck mass
• Refractory otitis media, epixtaxis, referred ear pain, cranial neuropathy
  • Most common cranial nerves affected are VI and V2 by tumor extension through foramen lacerum into cavernous sinus
• Syndromes:
  • Jacod's: compression of CN II-VI by extension into cavernous sinus, leading to ophthalmoplegia, blindness, and trigeminal neuralgia
  • Villaret: compression of CN IX-XII by parapharyngeal nodes, leading to difficulty swallowing (IX), altered taste (IX), unilateral Horner's (X), paralysis of sternocleidomastoid/trapezius (XI), hemiglossal paralysis (XII)
  • Vernet's syndrome (jugular foramen syndrome): compression of CN IX-XI by extension into jugular foramen, leading to difficulty swallowing, vocal cord paralysis, and paralysis of sternocleidomastoid/trapezius
  • Trotter's triad (Sinus of Morgagni): unilateral conductive hearing loss (eustachian tube), impaired ipsilateral soft palate motility, and mandibular pain

Anatomy

• Includes vault, lateral walls, and posterior wall
• Anterior border begins at the end of the nasal cavity, at the posterior choana (where nasal septum disappears). Radiographically this can be seen as the posterior wall of the maxillary sinus. It extends along plane of the airway to the level of free border of the soft palate posteriorly
• Lateral walls consist of the torus tubarius (Eustachian tube opening), pharyngeal recess (Fossa of Rosenmuller) posterior to torus tubarius, and behind these are the superior pharyngeal constrictor muscles, and behind this is the medial pterygoid plate.
• Superior border is the cribriform plate and sphenoid sinus. Clivus consists of part of the sphenoid bone (behind the sinus, the tail end of the sella turcica) and part of the occipital bone and forms the posterior border of the nasopharynx. Hard and soft palates (the inferior border) sits about C2.
• Eustachean tube passes through base of skull between foramen ovale and lacerum to reach nasopharynx
• Inferior border (floor) is the superior surface of the soft palate
• Cranial nerves are important since NPC may commonly extend along them intracranially:
  • Cavernous sinus - III, IV, V1 + V2 (not V3), VI - (all pass through superior orbital fissure except V2 is through foramen rotundum)
  • Foramen rotundum - V2
  • Foramen ovale - V3 - anterolateral to clivus
  • Foramen lacerum - lateral to front part of clivus - plugged with cartilage in vivo
  • Jugular foramen - IX, X, XI - lateral to foramen magnum
  • Hypoglossal canal - XII - lateral to foramen magnum
• Nearby is the tensor veli palatini, levator veli palatini
• Pharyngeal recess (Fossa of Rosenmuller)
  • Postulated to be the origin of most NPC cancers
  • Posterior to torus tubaris (posterior lip of the medial end of the cartilagenous eustachean tube)
  • Herniation of nasopharyngeal mucosa through deficiency between skull base and superior-most fibers of pharyngeal constrictors
  • PMID 1876886 (Full text for pictures): >50% are deeper than 1 cm (range 2mm - 19mm), and 90% are narrower than 5 mm. It points lateraly ~45% from sagittal plane

Pathology

WHO classification:

• Type I: keratinizing squamous cell carcinoma - 20%
• Non-keratinizing carcinoma
  • Type II: differentiated non keratinizing carcinoma (formerly transitional cell carcinoma) - 30-40%
  • Type III: undifferentiated non keratinizing carcinoma (formely lymphoepithelioma) - 40-50%
• Basaloid sqaumous cell carcinoma - recent distinction, appears aggressive with poor survival

Spread

• Spreads along walls of nasopharynx with local invasion
  • Can spread to cavernous sinus through foramen lacerum (and involve CN III-VI [except V3]).
  • Commonly has involvement of jugular foramen and hypoglossal canal (CN IX-XII).
• 65-90% have lymph node involvement at presentation
  • About 50% have bilateral lymph node involvement
  • Cervical Level IIb seem to be the first echelon nodes in NPC, closely followed by lateral retropharyngeal LNs
  • Retropharyngeal LN involvement is common, but difficult to detect on CT. In CT based studies, RLN were positive in 30-50%, while in MRI based studies this number may be as high as 80%
• Distant mets are less common at initial presentation but in recurrent disease are more common than in other H&N cancers.
  • Mets correlate more with nodal status than T stage.
  • Distant Mets by N stage: N1=10-20%, N2=30-40%, N3=40-70%.
• Spreads to bones > lungs, liver, and brain.

Retropharyngeal lymph nodes

• It is not clear whether these are staged as N0 or N1, with differences among institutions
• Prognosis for RLN+ N0 appears comparable to N1
• RLNs atrophy with age, and are usually obliterated by adulthood. Normal axial diameter in patients >40 year is ~3 mm. Therefore, some studies use minimal axial diameter >=5 mm on MRI as a size criterion for RLN mets
• Most RLN+ are located at C1 level, and incidence decreases steadily from C1 to C3
• It appears that afferent lymphatic vessels of lateral RLN in NPC begin in the parapharyngeal space (T2 tumors); lymphatic drainage of nasal cavity, oropharynx, and pharyngeal wall (and thus lymphatic drainage of T3 and T4 tumors) may be primarily to cervical lymph nodes

• Singapore; 2009 (1992-1994) PMID 19189339 -- "Retropharyngeal nodal metastasis related to higher rate of distant metastasis in patients with N(0) and N(1) nasopharyngeal cancer." (Tham IW, Head Neck. 2009 Feb 2. [Epub ahead of print])
  • Retrospective. 667 patients, NPC, Stage T2-4 N0-1. RLN+ in 47% by CT. Median F/U 8.3 years
  • Outcome: Patients with N0 and RLN+ had similar hazard for DM as patients with N1, and worse than patients with N0 and RLN-
  • Conclusion: Patients with N0 disease and RLN lymph nodes share similar prognosis as patients with N1 disease

• Fudan, China; 2009 PMID 18538502 -- "Patterns of retropharyngeal node metastasis in nasopharyngeal carcinoma." (Wang XS, Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):194-201. Epub 2008 Jun 4.)
  • Retrospective. 618 NPC patients. MRI staging. LN+ in 88%; RLN+ alone 6%, cervical LN+ alone 28%, both RLN and cervical LN 66%. Incidence of RLN lower 72% than cervical LN 93%
  • Location of RLN: occipital bone 6%, C1 76%, C2 17%, C3 0.5%. Incidence significantly higher with parapharyngeal involvement
  • Conclusion: Level IIb LNs seems first-echelon nodes in NPC; incidence of RLN mets decreases steadily in level

• Sun Yat-sen, China; 2007 PMID 17332287 -- "Retropharyngeal lymph node metastasis in nasopharyngeal carcinoma: prognostic value and staging categories." (Ma J, Clin Cancer Res. 2007 Mar 1;13(5):1445-52.)
  • Retrospective. 749 patients, NPC. RLN+ in 51% by CT
  • Outcome: On multivariate analysis, in N0 patients, RLN+ independent predictor for OS, LRFS and DMFS. No difference in unilateral vs bilateral RLN+. Survival if N0 and RLN+ similar to survival if N+
  • Conclusion: RLN mets affect prognosis in N0 patients, and should be classified as N1

Response to treatment

Despite rapid response to initial treatment, high incidence of local failure.

Treatment Overview

• Surgery plays only a minimal role due to significant potential morbidity
• Historically, RT alone was used, and resulted in 5-year OS 35-50%
  • Early-stage (I-II) outcomes were good, with 5-year RFS 75-95% and OS 70-80%
  • However, advanced-stage (III-IV) 5-year RFS was ~50%, and OS only 10-40%
• Early stage disease (Stage I-II) typically continues to be managed with RT alone
• Advanced stage disease (Stage III-IV) is managed with concurrent chemo-RT; it is not clear whether there is any benefit to further adjuvant chemotherapy

Surgery

• Due to deep location of nasopharynx, and anatomic proximity to critical structures, radical surgery is typically not used
• Role of surgery is initially for biopsy for histological confirmation
• It may also be used for management of the neck for persistently enlarged lymph nodes
• Finally, there may be role in persistent or recurrent disease