14. Etiology Normal Epithelium Low Grade Dysplasia High Grade Dysplasia Invasive Carcinoma Metastatic Carcinoma P53 Mutation Gain Chromosome 12 Deletion 11 and 13 Deletion of Chromosomes 3p and 9p Inactivation of Chromosome p14, 15 and 16 EBV infection
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17. Comparison Infratemporal fossa / cavernous sinus / PNS / direct invasion of C2 or C1 / anterior cranial nerves Pterygoid process / posterior cranial nerve / posterior cervical vertebrae / BOS / PPS beyond SO line Involving the nasal cavity, oropharynx, anterior cervical vertebrae, PPS before SO line Limited to nasopharynx Huaqing (1994) Bony destruction including eustachian tube No bony destruction Extending to two sites in nasopharynx Limited to one site in nasopharynx IUAC (1988) NA Bone/ Cranial nerve/ orbital / hypopharyngeal / infratemporal fossa involvement Extending to nasal fossa or oropharynx Confined to nasopharynx Ho (1978) Involving skull base or cranial nerves Beyond nasopharynx > 1 cm but confined to nasopharynx < 1 cm diameter Fletcher (1967) T4 T3 T2 T1 Staging System
The nasopharynx is a roughly cuboidal space, opening into the nasal cavity through the posterior choane anteriorly, and the oropharynx, inferiorly. The lateral and the posterior wall are bounded by the pharyngobasilar fascia, descending from the base of the skull. The roof contains abundant lymphomatous tissue special in children and the aggregate of lymphomatous tissue forms the pharyngeal tonsil in this age group. The Eustachian tube opens into the lateral wall of the nasopharynx, and the posterior cartilaginous edge of the same makes the bulge, which is known as the torus tubaris. Just posterior to this torus lies the fossa of Rosenmuller which is considered as the most common site for origin of nasopharyngeal carcinomas. This is the place where the nasopharynx is at it’s widest.
This diagram shows the base of the skull from below, and the close relationship of the foramen lacerum to the nasopharynx is immediately apparent. Since the foramen lacerum opens directly into the middle cranial fossa, It forms an important route by which nasopharyngeal cancers can spread into this area. In addition to this important foramen, other foramina in close relationship, include the foramen rotundum, which transmits the maxillary division of the trigeminal nerve, foramen ovale which transmits the mandible division of the trigeminal nerve, foramen spinosum, which transmits the middle meningeal vessels and the recurrent branch of the mandibular nerve. In addition to this the hypoglossal canal and jugular foramen are in close relationship posteriorly and serve as potential pathways of spread to the cranial nerves, particularly 9 th, 10 th , 11 th and 12 th .
Superiorly bound by the base of the skull and overlies the carotid canal, jugular foramen, and hypoglossal foramen. The inferior border is the junction of the posterior belly of the digastric muscle and the greater cornu of the hyoid bone. Medially, the boundary is made up of the buccopharyngeal or visceral fascia overlying the superior pharyngeal constrictors. The lateral boundary is made up of the fascia over the medial pterygoid muscle, the ramus of the mandible, the posterior belly of the digastric muscle, and the fascia over the retromandibular deep portion of the parotid gland. Anteriorly the limit is the pterygomandibular raphe. The posterior limit is the dorsal layer of fascia making up the carotid sheath. Fascia which extends from the styloid process to the tensor veli palantini muscle , called the tensor-vascular-styloid fascia, because it also contains the ascending palatine artery and vein, divides the parapharyngeal space into an anterolateral or prestyloid, and a posteromedial, or retrostyloid compartments . The prestyloid compartment contains fat, a portion of the retromandibular parotid gland, and some lymph nodes. The retrostyloid compartment contains the internal carotid artery, internal jugular vein, cranial nerves IX-XII, sympathetic chain, and lymph nodes. The parapharyngeal nodes superiorly are connected to the node of Rouviere in the lateral most retropharyngeal space.
The exact incidence of cranial nerve involvement varies from series to series being higher in Asian series and those using CT scans. 12% patients have clinically detected cranial nerve palsy while 29% have radiologically detected cranial nerve involvement.
Lymph nodes are involved at presentation in 89%. There is unilateral involvement in 39% and bilateral involvement in 51%. Low-grade squamous cell carcinomas produce fewer metastases (73%) than high-grade carcinomas (92%). Metastases to submental and occipital nodes may appear when there is blockage of the common lymphatic pathways either by massive neck disease or by an untimely neck dissection.
Inactivation of the tumor suppressor genes namely the Chromosomes 14, 15 and 16 are considered central steps in the pathogenesis of high grade dysplasia.
SO line is the line connecting the styloid process to the posterior edge of the foramen magnum.
Ho’s System was a better predictor of prognosis than the 1988 AJCC system but it failed to include the prognostic importance of parapharyngeal extension. Further 5 stages were given which was not same as the western standard. The new AJCC system includes the nodal staging of the Ho’s system which is of prognostic significance
Midline nodes are considered unilateral. Supraclavicular zone or fossa is relevant to the staging of nasopharyngeal carcinoma and is the triangular region originally described by Ho. It is defined by 3 points: (1) the superior margin of the sternal end of the clavicle, (2) the superior margin of the lateral end of the clavicle, and (3) the point where the neck meets the shoulder. Note that this would include caudal portions of Levels IV and V. All cases with lymph nodes (whole or part) in the fossa are considered N3b.
Stage IIa includes patients with T2a disease without neck nodes Stage IIb includes patients with N1 disease with T 1 – T 2a disease and also includes T2b disease without neck nodes. Stage III includes patients with T 1 –T2b disease with bilateral neck nodes or patients with T3 disease no, unilateral or bilateral neck nodes. Stage IVA includes patients with T4 disease while IVB includes patients with N3 disease Stage IVC stands for distant mets.
The Lymphoepitheliomas subtype consists of undifferentiated cells forming syncitial mass is along with which large number of small lymphocytes are interspersed. Some authors believe that this histology confers a higher local control rate, as well as better prognosis than squamous cell carcinoma. Overall, it has been found that patients with undifferentiated histology have a higher proportion of advanced stage at presentation.
The biological markers include IgA , IgE , anti-VCA often are predictors of relapse. Similiarly high ADCC levels are correlated with a better prognsis.
Fletcher at all in their textbook recommended that parallel opposing fields should not be used in the entire treatment course, unless photos of energy 20 MeV or higher are available.
Most commonly used technique and easiest to use. Also set up is a lot easier. As per Perez et al the superior border extends along a line joining the lateral canthus of the eye to the helix of the ear.
Shielding is done for the external auditory meatus and the oral cavity upto the third molar tooth to avoid hearing problems and oral mucositis.
Advantage is more homogenous dose distribution and coverage in the posterior cervical and lower supraclavicular nodes.
As the lower and superior fields are abutted so an area of high dose created on the deeper structures e.g. spinal cord.
Advantages of the posterior tilt: Reduced dose to the opposite eye Direct irradiation of ipsilateral and middle ear avoided ( when posterior border is situated in front of the external auditory canal only). In addition it enhances the posterior coverage at the basi-occiput Fletcher writes – “ In case posterior margin of the portal is located behind the external auditory canal no posterior tilt is necessary”
Electrons are simple to use but have the disadvantages viz.: Skin sparing advantage is absent. Hot spot develop in the region of the photon field abutting the electron field Small cold spot develops under the electron field edge abutting the photon field Dose to the posterior surface of the neck is increased.
This technique is best when high energy beams are not available and cannot be used when there is posterior extension into the base of skull as well as inferior extension into the oropharynx.
This technique is used for boosting the nasopharynx in the early disease T1 and T2 disease preferably. A oral stent is usually used to pust the tongue away from the palate and reduce the oral mucosal dose.
In effect the hyperextension of the head allows the orbital floor and the base of the skull to become parallel to the beam edge.
As this dose distribution shows using the 4 field approach allows us to spare the TM joint and the parotid while at the same time allows us to increase the dose to nasopharynx and para nasopharyngeal tissues. Anterior facial fields are used for boosting the nasopharynx – preventing excess dose to the TM joints S/C tissues and the ear.
The CTV included the anterior table of clivus, 5mm of normal oropharynx below the GTV, the entire sphenoid sinus floor, the parapharyngeal space including both medial and lateral pterygoid muscles, the pterygoid plates, the pterygomaxillary fissures, and the posterior part of nasal cavities, 5 mm anterior to the GTV.
Lee AWM, Poon YF, Foo W, et al. Retrospective analysis of 5037 patients with nasopharyngeal carcinoma treated during 1976±1985. Overall survival and patterns of failure. Int J Radiat Oncol Biol Phys 1992;31:261±270. Lee AWM, Law SCK, Foo W, et al. Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976±1985: survival after local recurrence. Int J Radiat Oncol Biol Phys 1993;26:773±782.
BED = 41.25 Gy for late reaction ( α / β = 3 Gy) for the boost phase. For the initial phase the dose is 66.67 Gy for late reactions. The total BED is 107.52. For 66 Gy in 33# for late reactions BED ~ 110
With 2DRT alone, the 5-year local relapse-free survival was in the range of 75–95% for UICC T1-T2 stages and 45–80% for UICC T3-T4 stages, and the overall survival was in the order of 50–70% for all stages
However a trial conducted by Lee et al found that a 6 day course of radiotherapy did indeed confer an advantage in terms of local control. Thus it can be concluded that the SLD repair times of at least > 6 hrs are necessary and any BID RT course should be avoided as a high chance of neurological sequelae exist.
At the same time, several other alternative, brachytherapy techniques were also developed by other authors, notably Cade who had used, a linear array of radium tubes inside catheters and for paris where radium needles packed in gauze was used for brachytherapy. However the bulky size of the applicators, inconstant dosimetry and discomfort associated with prolonged application made this form of brachytherapy unpopular.
The Forzhou catheters are made from rubber and obviate the need for requiring expensive catheters. Their design mimics the Levendag applicator.
This technique by Pierquin as early as 1963.
A pair of feeding tubes, is inserted through the nasal cavity and brought out through the oral cavity. To this is fixed a dummy applicator, which contains the silicone gel. This silicone gel is quick setting and takes the shape of the nasopharynx quickly. One this has been done. The silicone gel mould is brought out and a negative plaster of Paris cast in made from this. Using acrylic, a fresh mould is prepared from this negative plaster of Paris, which is usually 3-5 mm thick. The surface is smoothened and the edges are whittled away. Grooves are ground in this mould, in which catheters are placed. A careful note is made of the catheter length, and the end towards the oral site remains blind. Two rubber strips are inserted towards the nasal end of acrylic applicator in order to fix the applicator to the nasal cavity. Again the feeding tubes are brought out through the oral cavity, and the applicator is placed upside down and fixed to these feeding tubes by the means of the catheters and the rubber strips. Using a detractor the palate is retracted upwards, and traction is placed upon the lateral students. In order to drag the applicator into position, snugly in the nasopharynx. The rubber bands are tied in front of the nasal septum, while buttons are threaded through the plastic tubes which are brought out through the nasal cavity.
In addition to the design of the applicator Prof Levendag also defined several dose points which corresponded to the normal tissue doses. This was necessary as he was using ICBT after delivering doses in the range of 60 Gy in absence of parapharyngeal extension to 70 Gy in the presence of the same
The divergence of the tubes is due to the fact that the separation between the two tubes at the base is 22.5 mm and at the nose it is 14 mm. So the plane of the two tubes are converging at the sagittal plane. The procedure of insertion is straightforward and consists of a pull and push technique – usually performed under local anesthesia.
While taking the simulation films 2 lead markers are placed – one at the tragus of the ear and the other at the lateral canthus of the contralateral eye. A Line (Line 1) is drawn joining these two points. A second reference line joins the anterior clinoid process and the ventral part of the body of the C1 vertebrae ( Line 2). Orthogonal isocentric fields are taken and the points are marked on the lateral film and projected on the AP film using the TPS. The tumor points are marked as follows: Point R corresponds to the ventral part of the body of the C1 vertebra. The point of intersection of line 1 and line 2 on the lateral radiograph gives the BOS point. The intersection of the line which joins the BOS point to the end of the hard palate on the with the bony skull base is taken as the Na point. Dose is prescribed at the Na point and the dotted line represents the 3 Gy isodose line. Usually this point is situated at a distance of 0.75 cm from the sources. On the AP film both the Na and BOS points are situated 1.5 cm to the midline on the AP view. The Normal Tissue points are defined as follows: Re – The retinal points are situated 1 cm posterior to the point on the outer canthus along line 1 and situated 2.5 cm on either side of midline. C point – Situated along the posterior border of the C1 vertebrae behind the R point Pa point – Situated at the posterior edge of the hard palate and situated 1 cm from the midline. P point – Situated 0.5 cm below the anterior clinoid process along the line 2. OC point – Situated 1.5 cm in front of the anterior clinoid process. No point – Situated on a line drawn perpendicular to the source from the retinal point 0.75 cm below the source.
Advantages : Shrinks nodal volume in time to initiation of therapy Potential to assess tumor sensitivity Some treatment given during waiting period Disadvantages : Delays initiation of radiotherapy Temporal profile of side effects altered – impaired dose delivery May allow selection of resistant clones – triggering accelerated repopulation.
The incidence of severe complications was related to the total cumulative dose of external beam irradiation; 4% for patients receiving doses less than or equal to 100 Gy compared with 39% for those patients who received doses greater than 100 Gy ( p =0.066). The recommendation is an additional salvage 20–30 Gy in 10–15 fractions to the nasopharynx, to limit the total dose of external irradiation to less than 100 Gy. Intracavitary brachytherapy is then used to deliver an additional 40–50 Gy to the surface of the recurrent cancer. Serious CNS sequelae may be seen in as high as 12% Most common complications: Soft tissue necrosis in nasopharynx, osteonecrosis of sphenoid sinus.
Wei et al reported on the use of gold grains.
The importance of neurological Sequelae in determining the overall long-term morbidity in patients with none of nasopharyngeal cancer is demonstrated by the findings Lee and associates, who treated over 4000 patients with radiation therapy, delivering 65 GY to nasopharynx and 53 GY to the cervical lymph nodes. 10% of the patients had developed neurological Sequelae, and these accounted for 59 of 62 (95%) treatment-related deaths in their population.
