1. Nasopharyngeal tumours
ENT Department
Registrar FRCS Teaching
Freeman Hospital
Newcastle
April 2010
Cameron Davies-Husband
MBBS, BSc (Hons), MRCS (Eng), DOHNS (Eng), PGCert

2. Aims To provide an overview of nasopharyngeal carcinoma, including:
Pathology
Symptoms
Diagnosis
Treatment

3. Introduction Nasopharyngeal carcinoma:
non-lymphomatous, squamous-cell carcinoma occurring in the epithelial lining of the nasopharynx.

4. Relevent anatomy Nasopharynx is located below the central skull base
The sphenoid sinus forms the roof
The roof slopes posteriorly with the basiocciput and upper cervical spine forming the posterior wall
The lateral nasopharynx wall is formed by:
the medial pterygoid plate,
the palatal muscles,
the torus tubarius
the fossa of Rosenmuller
The soft palate separates the nasopharynx from the oropharynx.
The fossa of Rosenmuller is located superior and posterior to the torus tubarius

5. Relevent anatomy

6. Modes of spread Anterior:
Infiltration of pterygopalatine fossa through the sphenopalatine foramen9
Earliest sign of involvement of the pterygopalatine fossa is obliteration of the normal fat content

7. Modes of spread Anterior:
Perineural spread along the mandibular nerve can seen to extend into the intracranial cavity through the foramen rotundum
The tumour can infiltrate further superiorly into the inferior orbital fissure and subsequently extend into the orbital apex

8. Modes of spread Lateral:
Partial or complete effacement of the fat-filled parapharyngeal space
The mandibular nerve is often infiltrated.
Posterolateral spread into the retrostyloid compartment may result in the infiltration of the carotid space placing cranial nerves IX, X, XI and XII at risk12,13.

9. Epidemiology
Uncommon: age-adjusted incidence for both sexes is < 1 per 100, 000 population1
Occurs with much greater frequency in:
Southern China
Northern Africa
Alaska
Incidence among men and women in Hong Kong is 20–30 and 15–20 per , respectively1
Lower among Chinese people born in North America7,8

10. Pathology Tumour cells are of squamous origin10
The undifferentiated carcinoma is a form of squamous-cell carcinoma11
EBV-encoded RNA signal has been shown, by in-situ hybridisation, to be present in nearly all tumour cells12
Premalignant lesions also harbour EBV12

11. Pathology Histological classification; WHO (1978)15:
Type I: typical keratinising squamous-cell carcinomas
Type II: non-keratinising squamous carcinomas
Type III: undifferentiated carcinomas
The second classification is correlated with EBV serology:
Squamous-cell NPCs have reduced EBV titre
Undifferentiated NPCs have raised EBV titres.

12. Pathology In North America: In Southern China:
25% of tumour patients have type I histology
12% have type II
63% have type III.
In Southern China:
2% of tumour patients have type I histology
3% have type II
95% have type III17

13. Classification Keratinising squamous-cell carcinoma (WHO type I)
Non-keratinising carcinoma
Differentiated non-keratinising carcinoma (WHO type II)
Undifferentiated carcinoma (WHO type III)

14. Symptoms

15. Symptoms (1) presence of tumour mass in the nasopharynx
(2) dysfunction of the eustachian tube, associated with the lateroposterior extension of the tumour to the paranasopharyngeal space
(3) skull-base erosion and palsy of the fifth and sixth cranial nerves, associated with the superior extension of the tumour
(4) neck masses, usually appearing first in the upper neck, associated with metastases

16. Symptoms
A retrospective analysis of 4768 patients identified symptoms of nasopharyngeal carcinoma at presentation21:
Neck mass (76%)
Nasal dysfunction (73%)
Aural dysfunction (62%)
Headache (35%)
Diplopia (11%),
Facial numbness (8%)
Weight loss (7%)
Trismus (3%)

17. Symptoms Physical signs present at diagnosis included21,22:
Enlarged neck node (75%)
Cranial nerve palsy (20%)
3rd, 5th, 6th, and 12th nerves
Investigations:
EBV serology
EUA & PNS biopsy
Cross sectional CT/MRI

18. Imaging studies Cross sectional CT:
Paranasopharyngeal spread: one of the most common modes of NPC extension28
Perineural spread (through the foramen ovale)
Important route of intracranial extension28
Cavernous sinus involvement without skull-base erosion29

19. Imaging studies
MRI > CT for displaying both superficial and deep nasopharyngeal soft tissue and for differentiating tumour from soft tissue.
MRI is also more sensitive for assessment of retropharyngeal and deep cervical nodal metastases30
CT should be undertaken when the status of the skull base cannot be satisfactorily established with MRI31
MRI is able to detect marrow infiltration by tumours, whereas CT cannot (associated with an increased risk of distant metastases32)

20. Imaging studies Distant metastases:
Bone scans33 liver scintigraphy34 abdominal ultrasonography35 and marrow biopsy36 are of little value in routine staging
No evidence to lend support to distant imaging for low-risk (N0 or stage I) disease
High-risk (N3) disease should be fully staged with chest radiography, bone scan, and liver ultrasonography37
The role of PET scanning is established, but it’s value has not been ascertained38

21. Imaging studies Monitoring post treatment: Both CT and MRI have:
Low sensitivity41
Moderate specificity41
MRI generally better at detecting tumour recurrence and post radiotherapy complications42
PET reported to be more sensitive then CT/MRI at detecting recurrent/residual tumours43

22. Staging
American Joint Committee on Cancer Staging and End Result Reporting/International Union Against Cancer (AJC/UICC)
Preferred staging system in USA/Europe
Revised in 1997:
Enabled patients to be staged more sensitively55
Provided a better predictor of survival than the old system56

23. Staging T1 + T2  new “T1” tumours ~ confined to nasopharynx
T2 tumours ~ involving nasal fossa, oropharynx, or paranasopharyngeal space
T3 tumours ~ extension to the skull base/paranasal sinuses
T4 tumours ~ extended into the infratemporal fossa, orbit, hypopharynx, and cranium, or to the cranial nerves

24. Staging N1: unilateral nodal involvement
N2: bilateral nodal disease that has not reached N3 designation, irrespective of the size, number, and anatomical location of the nodes
N3: lymph nodes larger than 6cm (N3a), or nodes that have extended to the supraclavicular fossa (N3b)54

25. Prognosis Tumour extent ~ TNM classification
Size/degree of fixation of lymph nodes57
Patient gender57
Patient age57
The presence of cranial nerve palsy57
Ear symptoms at presentation57
Histological type58
Radiotherapy dose and coverage58
Paranasopharyngeal extension59

26. Prognosis
Estimated 1% increase in risk of local failure for every 1 cm3 increase in primary tumour volume63
Quantitative analysis of circulating EBV DNA in NPC positively correlates with disease stage, as well as exhibiting prognostic importance64

27. Prognosis T1–2 N0–1 (relatively good treatment outcome)
T3–4 N0–1 (mainly local failure)
T1–2 N2–3 (mainly regional and distant failure)
T3–4 N2–3 (local, regional and distant failure)
Early evidence that for advanced diseases, adding chemotherapy to radiotherapy will improve treatment outcome, both in terms of locoregional control and distant metastases66,67

28. Treatment
Radiotherapy: the standard treatment for nasopharyngeal carcinoma
Dose-limiting organs at risk:
brain stem, spinal cord, pituitary-hypothalamic axis, temporal lobes, eyes, middle and inner ears, and parotid glands

29. Treatment Radiotherapy approaches: Phase I treatment:
Large lateral opposing faciocervical fields that cover the primary tumour and the upper neck lymphatics in one volume
Matching lower anterior cervical field for lower neck lymphatics
When the spinal cord dose reaches 40–45 Gy  phase II treatment

30. Treatment Phase II treatment – either:
Lateral opposing facial fields with anterior facial field for the primary tumour, with matching anterior cervical field
Lateral opposing facio-cervical fields but with shrinkage of fields to avoid the spinal cord68,69

31. Treatment Radiotherapy tumour control:
T1-T2: 75–90%
T3-T4: 50–75%65,68,69,70,71
Radiotherapy nodal disease control:
N0-N1: 90%
N2-N3: 70%65
Note: high incidence of occult neck node involvement - prophylactic neck radiation is usually recommended73

32. Treatment
Good locoregional control should be the prime objective of treatment
Locoregional relapses represent a significant risk factor for the development of distant metastases74
For T1-T2 tumours, a booster dose via intracavitary brachytherapy improved tumour control by 16%75

33. Treatment Intensity modulated radiotherapy (IMRT)
Overcomes major limitations of 2D planning78,79
Improves the dose differential between the tumour and the dose-limiting organs81,82
Resolves the problem of dose uncertainty at the junction between the primary tumour and neck lymphatic target volumes as it enables the primary tumour and the upper neck nodes to be treated in one volume throughout
Excellent locoregional control of nasopharyngeal carcinomas83

34. Chemotherapy
Twelve RCT’s have reported on neoadjuvant, concurrent, and adjuvant therapy, or on a combination of these approaches.
Nine were reported before 2004 and included four neoadjuvant chemotherapy studies,91–94 three concurrent chemotherapy studies,66,67,95 and two adjuvant studies96,97
One of the concurrent studies95 has recently been updated,98 and two of the neoadjuvant studies92,93 have been updated and pooled for meta-analysis99
Three more concurrent chemotherapy studies have been reported from Hong Kong and Singapore100–102

36. Chemotherapy Meta-analysis99 Adjuvant studies96,97:
Improvements in relapse-free survival and disease specific survival
Overall survival was not improved
Adjuvant studies96,97:
No improvement either in relapse-free survival or overall survival
Of the three basic approaches tested (neoadjuvant, concurrent, and adjuvant chemotherapy), concurrent chemoradiotherapy is the most efficacious…

37. Follow-up Confirmation of disease remission:
Clinical examination
Endoscopic examination (+/- biopsy)
Imaging studies
Residual tumours can be treated with either:
Cone down fields111
Brachytherapy112
Residual neck node disease is amenable to radical neck dissection.

38. Follow-up
Regular imaging every 4–6 months during the initial 3–5 years after treatment is advised 114,115
Endoscopic examination to detect superficial tumours
Cross-section imaging to detect deep infiltrating tumours not associated with mucosal lesion31
PET superior to MRI for detection of residual and recurrent tumour46

39. Follow-up
Circulating free EBV DNA has been reported in patients with nasopharyngeal carcinoma117
Quantities of EBV DNA copies before and after treatment are significantly related to the rates of overall and disease-free survival119
Serum EBV DNA shown to be more sensitive and reliable than other options for the detection of distant metastases116

40. Follow-up
Levels of post-treatment EBV DNA compared with pre-treatment EBV DNA are a good predictor of progression-free survival120
Raised EBV DNA detected in only 67% of patients with locoregional recurrence,116,122
In those with distant metastasis levels of EBV DNA copies were heightened before the appearance of clinical abnormality116

41. Management of residual/recurrent disease
Notoriously difficult to confirm because only clusters of tumour cells are present140
Survival after re-treatment for more extensive disease remains poor, but is still higher than in patients receiving supportive treatment only113

42. Recurrent disease in the neck
After combined chemoradiation for nasopharyngeal carcinoma, isolated failure in the neck is less than 5%146
Further course of external radiotherapy: the overall 5-year survival rate is around 20%147
Radical neck dissection: 5-year tumour control rate of 66% in the neck and a 5-year survival of 38%142
Radical neck dissection PLUS brachytherapy if tumour spreads beyond lymph node148

43. Recurrent disease in the nasopharynx
Can be managed with a second course of external radiotherapy
The dosage should be greater than the initial radiation dose
Incidence of late sequelae after re-irradiation is 24% with treatment mortality of 1·8%149
Small localised tumours:
Stereotactic radiotherapy (2-year local tumour control rate of
72%77)
Brachytherapy (5-year local tumour control rates were 87% and 63% for persistent/recurrent tumours respectively)
Surgical resection

44. Recurrent disease in the nasopharynx
Extensive disease
Nasopharyngectomy
5-year actuarial control of tumours in the nasopharynx is about 65%
5-year disease-free survival rate is around 54%.159,160

45. New developments Gene therapy: Immune therapy:
Replication-deficient adenovirus vector; transgene expression is under the transcriptional regulation of oriP of EBV has been reported174
Immune therapy:
Augmentation of cytotoxic T-lymphocyte responses175
Adoptive transfer of autologous EBV-specific cytotoxic T-cells176