Guidelines for radiotherapy of nasopharyngeal carcinoma

Abstract

With the extensive application of intensity-modulated conformal radiotherapy and the deepening of the concept of comprehensive treatment, the therapeutic effect of nasopharyngeal carcinoma and the quality of life of patients have been significantly improved. However, guidelines for radiotherapy of nasopharyngeal carcinoma in China are in short supply. Dozens of experts from the Radiation Oncology Physicians Branch of the Chinese Medical Doctor Association and the Radiation Oncology Branch of the Chinese Medical Association have developed the publication Guidelines for radiotherapy of nasopharyngeal carcinoma in China after discussion. The guidelines include the epidemiology, diagnosis, clinical stage, treatment principle, and treatment of complications of radiotherapy of nasopharyngeal carcinoma. Importantly, the procedure of radiotherapy for nasopharyngeal carcinoma has been developed, which covers the imaging of nasopharyngeal carcinoma, radiotherapy localization, target area delineation, dose limitation, and plan evaluation. The guidelines will help to realize the homogenization of the diagnosis and treatment of nasopharyngeal carcinoma among radiotherapeutic medical staff in different levels of hospitals in China, thereby improving the overall level of diagnosis and treatment of nasopharyngeal carcinoma in China.

INTRODUCTION

Nasopharyngeal carcinoma (NPC) cases are rarely seen globally, and exhibit a distinct geographic distribution. The highest incidences of NPC have been reported in southern China and South-East Asian (namely the south-west Pacific), followed by North Africa. In contrast, NPC cases are rather rare in Europe, America, and/or Oceania, with incidence rates of less than 1/100,000 person-years.¹ NPC incidences differ between regions in China, revealing relatively high incidence in the south but low incidence in the north. High morbidity due to NPC has been reported in south and south-west China, including Guangdong, Guangxi, Hainan, Jiangxi, Hong Kong, and Macao. In terms of demographic trends, the male-to-female incidence ratio is 2.4:1 to 2.8:1, with a peak incidence at around 40–59 years of age. Racial susceptibility and familial aggregation have also been observed among NPC patients. Recently, there has been a gradual decline in NPC incidence worldwide. The etiology of NPC has not yet been determined, and it is currently considered to be a polygenic hereditary disease (inherited or acquired) involving interactions between multiple genes and/or between genes and environment. Epstein-Barr virus (EBV) infection, chemical carcinogens, environment, and heredity have been recognized as contributing factors for the pathogenesis and development of NPC.² Genomic variations have also been shown to contribute to NPC development: multiple loss-of-function mutations in the nuclear factor kappa beta (NF-kB)-negative regulators, recurrent genetic lesions (including loss of the cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/CDKN2B) locus, cyclin D1 (CCND1) amplification, tumor protein 53 (TP53) mutation, and mutations in the phosphatidylinositol 3-kinase (PI3K)/MAPK (mitogen-activated protein kinase) signaling pathway), chromatin modification, and deoxyribonucleic acid (DNA) repairing, etc.³ Nowadays, radiotherapy or radiotherapy-based comprehensive treatment has been recognized as the most valid and radical treatment for NPC. Benefit from the wide usage of intensity-modulated radiotherapy (IMRT), both the local control and overall survival rates of NPC have been improved significantly, and consequently distant metastasis has turned into the major failure mode. Tumor pharmacotherapy has developed rapidly in recent years, including chemotherapy, moleculary targeted therapy, immunotherapy, and radiosensitizers. Based on these findings, it is extremely important to develop Chinese practice guidelines for radiotherapy of NPC, the popularization and application of which in clinical practice would provide a reference for clinicians to formulate treatment strategies for NPC, ultimately benefiting the majority of NPC patients.

CLINICAL PRESENTATION

The clinical presentations of NPC are complicated and protean, depending on the site of invasion, with or without lymph node or distant metastasis.

Symptoms Epistaxis

Epistaxis is one of the typical manifestations of early exogenous NPC, which occuring in the morning commonly. Nasopharyngeal hemorrhage occurs in a few patients.

Tinnitus and hearing loss

A unilateral auricular symptom is one of the early clinical manifestations of NPC. Ear dullness, congestion, tinnitus, and hearing loss are common complaints.

Nasal obstruction

Progressive rhinobyon (unilateral or bilateral) appears. Mouth breathing occurs in severe cases.

Headache

Headache is one of the most common symptoms among NPC patients. The location and severity of the headache depend on the lesion site and extent. Persistent migraine is frequently observed, while calvaria, occiput posterior, and/or collar pain are relatively rare.

Facial numbness

Tumor encroachment or compression on the trigeminal nerve can cause superficial paresthesia. Ant crawling feeling, tactile sensitivity or numbness may be observed on the skin controlled by the trigeminal nerve.

Diplopia and ocular symptoms

Tumor compression, invasion of the II, III, IV, and VI cranial nerves or invasion of orbit, forming occupying retrobulbar or intrabulbar space, results in diplopia and other ocular symptoms.

Signs Neck masses

Neck lymph node metastasis has been reported in 60–80% of patients with NPC. Asymptomatic neck mass has been reported in 40–50% of NPC patients at the initial consultation. In addition to local mass, some patients present other symptoms caused by neck blood vessel compression and neurothlipsis.

Nasopharyngeal masses

A swollen nasopharynx can be detected using an indirect nasopharyngoscopy or a nasopharyngo-fiberoscope. For submucosal tumors, conspicuous nodules are not always visible, and the nasopharyneal mass could be asymmetry.

Manifestations of cranial nerve invasion

Once the NPC invades the skull base or brain, the base of the skull or adjacent structures within the skull is vulnerable to damage. In addition to headache, symptoms and/or syndromes caused by cranial nerve injury may occur. For example, supraorbital fissure syndrome, orbital apex syndrome, pituitary sphenoid sinus syndrome, cavernous sinus syndrome (foramen rupture syndrome or sphenoid sinus syndrome), jugular foramen syndrome, hypoglossal foramen syndrome, and posterior parotid space syndrome are common.

AUXILIARY EXAMINATIONS Laboratory examinations General examinations

General examinations include blood routine, liver and kidney function, electrolytes, blood glucose, coagulation function, thyroid function, urine routine, and stool routine examinations.

Blood Epstein–Barr virus detection

Plasma EBV-DNA copy number detection is an important auxiliary means for early screening, prognosis judgment, efficacy evaluation, and follow-up review of NPC.⁴

Imageological examinations MRI/CT

Magnetic resonance imaging (MRI) is advantageous in determining the location of the primary tumor and evaluating the intracranial structure and the involvement of the posterior pharyngeal space.^5–7 The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) of NPC staging (8th edition) adopts MRI as the preferred imaging method.⁸ Those patients who cannot undergo MRI examination may receive computerized tomography (CT) examination of the primary tumor.

Chest and abdomen CT or abdominal MRI

Chest and abdomen CT or abdominal MRI is mainly used for the detection of the lung and liver metastases.

Ultrasound examination

Ultrasound examination is mainly used for evaluation of the metastasis of cervical lymph nodes and/or abdominal viscera.

Whole-body bone imaging

Whole-body bone imaging is a preliminary screening method for bone metastasis. When the bone emission computed (ECT) is positive, the X-ray, CT or MRI can be employed to further confirm.

PET/CT

Positron emission tomography-computed tomography (PET/CT) assists the diagnosis of early NPC lesions through tumor-related metabolism and other conditions, which has important application value for the determination of metastatic cervical lymph nodes and the discovery of systemic reclusive distant metastasis.⁹ PET/CT is especially recommended for patients at high risk for metastasis.

Electron/fiber nasopharyngoscopy

Electron/fiber nasopharyngoscopy is one of the most essential methods diagnosing NPC and may reveal abnormal nasopharyngeal lesions, such as masses, ulcers, necrosis, and epistaxis. Nasopharyngeal microscopy can directly observe the growth site of a nasopharyngeal tumor and the invasion of surrounding structures (such as the nasal cavity and oropharynx). Most important of all, biopsy with the help of fiber nasopharyngoscopy can lead to a pathological diagnosis.

Other examinations

Oral, oropharyngeal, hearing, vision, and other specialized examinations should be employed according to corresponding clinical symptoms. Related examinations (such as electrocardiogram, pulmonary function, and echocardiography) can be performed based on clinical need.

DIAGNOSIS Clinical diagnosis

The patients develop the symptoms and signs described above, and meet one of the following criteria:

Positive in EBV examination

EBV positiveness with cervical lymph node metastasis, with no detected masses.¹⁰

Nasopharyngoscopy

Submucosal bumps or cauliflower nodules, masses, bleeding, and necrotic objects are observed in the nasopharynx, oropharynx or nasal cavity by indirect or fiberoptic nasopharyngoscopy.

CT, MRI, and PET/CT examination

Nasopharyngeal lumen mass, localized or diffused thickening of the bilateral and posterior walls of nasopharynx, and shallow or disappearing of the pharyngeal fossa are presented. High intake of fluorodeoxyglucose in PET/CT.

Pathological diagnosis

NPC originates from nasopharyngeal mucosa, which has been confirmed to have squamous epithelial differentiation by light microscopy and ultrastructure. NPC can be divided into four types based on gross morphology: nodular, cauliflower, ulcerative and submucosal infiltrating. Usually, the nodular type is most commonly seen. The histological types are divided into keratinized squamous cell carcinoma, non-keratinized squamous cell carcinoma, and basal cell squamous cell carcinoma according to the World Health Organization (WHO) classification (2003). Other types of NPC include adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and malignant pleomorphic adenoma.²

Tumor staging in NPC

NPC is clinically staged using the TNM staging classification. To achieve the unification of different staging systems and promote the data exchange between international research centers and those in China, the current clinical staging standard for NPC represents the 8th edition of the AJCC/UICC staging system, which is as the same as the latest 2017 China NPC staging system recommended by the Chinese Committee for Staging of NPC.^8,10 Although the 8th edition of the AJCC/UICC staging system has better prognosis prediction and treatment guidance compared with the 7th edition, it still needs further improvement.¹¹ The prognostic significance of several situations [such as the T0 classification, tumor invasion of unusual structures (parotid gland, cervical spine and parotid lymph node metastasis, etc.) and nodal extracapsular spread] needs further evaluation to provide a better foundation for precise and individualized treatment (Appendix I).^12–15

TREATMENT PRINCIPLES

Treatment of stage I (T1N0M0) NPC

Definitive radiotherapy to nasopharynx and elective radiotherapy to neck alone can achieve satisfactory results.

Treatment of stage II (T0-2N0-1M0) NPC

Whether concurrent chemotherapy is necessary for patients undergoing radiotherapy remains controversial. Patients at stage T2N1 have a high incidence of distant metastasis. For patients suitable for chemotherapy, concurrent chemotherapy using cisplatin is recommended,¹⁶ for patients who are intolerant to cisplatin, other platinum drugs are recommended,¹⁷ and for patients who are not suitable for chemotherapy, radiotherapy alone is recommended.

Treatment of locally advanced (stage II-IIIA) NPC

It is recommended to combine systemic therapy with radiotherapy, in which platinum-based concurrent chemotherapy is applied as the primary treatment method.¹⁸ Additional neoadjuvant or adjuvant chemotherapy can increase the treatment intensity.^19–21 In addition, for patients who cannot tolerate or are unwilling to receive chemotherapy, radiotherapy combined with targeted therapy (such as cetuximab, nimotuzumab,²² recombinant human endostatin,^23,24 etc.) and immunotherapy represents an alternative option.

Treatment of recurrent NPC

According to the suggestion of the multidisciplinary team (MDT), radiotherapy, surgery, chemotherapy, targeted therapy, immunotherapy and/or other treatment methods should be reasonably used for different conditions with an individualized comprehensive treatment strategy, effectively improving efficacy while maintaining the patient's quality of life.

Treatment of metastatic NPC

Patients can be further divided into the following two types based on the different treatment strategies and prognosis: patients diagnosed as metastasis for the first time and those with metastasis after treatment. For the former cases, systemic and local treatment should be considered to be equally important; for the latter, implementing reasonable stratified treatment and systemic treatment combined with local treatment represents the main treatment method.

Radiotherapy

Radiotherapy techniques for NPC include intensity-modulated radiotherapy, volumetric modulated arc therapy, and helical tomotherapy. More evidence is still needed for the application of proton or carbon ion intensity-modulated radiotherapy in the evaluation of NPC in clinical practice.

Positioning technical regulations

NPC patients usually lie in the straight supine position on a CT scan bed with an appropriate headrest (standard plastics pillow, water-activated pillow, traditional target-type vacuum cushion or individualized polyurethane foam sealing agent pillow).²⁵ The horizontal plane of the body is parallel to the bed plane, and the sagittal plane is perpendicular to the bed plane. The head, neck, and midline of the body are in a straight line to ensure the center symmetry of the body position. The arms are naturally placed parallel to both sides of the body, keeping both the left and right shoulders at the same height and the legs straight. The head and neck are immobilized by a 4–5 fixation point thermoplastic mask covering from skull vertex to shoulder. The scanning center should be close to the center of the target volumes, and the marking point should be in the flat area (avoiding the tip of the nose or submental) to ensure good positioning repeatability. In addition, an oral supporting articulator can be used to reduce oral adverse reactions, protecting the taste and controlling the mandible angle to reduce head and neck positioning errors. All patients are scanned with 2–3 mm serial slices from the vertex to 2 cm below the suprasternal notch, including both shoulders. CT acquisition should ideally be made with intravenous iodine contrast enhancement in the absence of contraindications to contrast agents. Moreover, the planning CT should be fused with the MRI based on matching the principle of bone landmarks.

MRI must be used for the delineation of the target volumes. For accredited radiation oncology centers, it is recommended that the MRI simulation uses the same position, scan center, slice thickness, and range as the CT simulation.

Delineation of the target volumes (sample graph) Delineation of the target volumes in radical radiotherapy

The target volumes for NPC irradiation include the gross tumor volume of the NPC (GTVnx), the gross tumor volume involving lymph nodes (GTVnd), and the clinical target volume (CTV), protecting the organs at risk as much as possible. Delineation of the primary tumor target volumes is performed according to the MRI, CT, and PET/CT. The delineation of CTV covers the sites at relatively high, medium or low risk of involvement based on the local progress.^26–28

• GTVnx. Grossnasopharyngeal tumor volume is seen in clinical and imaging examination.
• GTVnd. Gross tumor volume involving lymph nodes is seen in clinical and imaging examination. Multiple GTVnds can be set according to the complicated cervical lymph node conditions.
• CTV1. Clinical target volume 1 includes the GTVnx and surrounding subclinical lesion area (add 5 mm expansion from the GTVnx).
• CTV2. Clinical target volume 2 includes the CTV1 and surrounding 5-mm expansion, GTVnd, and potential cervical lymph node metastasis area.

Delineation of the target volumes in radical radiotherapy after induction chemotherapy

Induction chemotherapy (IC) is widely used in patients with locally advanced NPC and the effective rate of the classic first-line regimen is about 75%. The delineation of target volumes for patients undergoing IC is slightly different from those without IC.²⁹

• GTVnx. The soft tissue area in the gross tumor volume is delineated according to clinical and imaging examinations after IC, while the skull base bones are delineated according to clinical and imaging examinations before IC.
• GTVnd. Gross tumor volume involving lymph nodes is delineated according to clinical and imaging examinations after IC.
• CTV1 and CTV2. The delineation rules of clinical target volumes 1 and 2 are basically the same as those in radical radiotherapy. CTV1 should include the tumor shrinking part of the soft tissue area after IC.
• CTVnd. The delineation rules of the clinical target volume involving lymph nodes are basically the same as those of CTV2. If there is nodal extracapsular spread or invasion of the surrounding muscles, CTV1 can be set according to the specific situation.

Dosimetric recommendation

According to the primary nasopharyngeal lesions, subclinical nasopharyngeal lesions, cervical lymph nodes, and cervical lymphatic drainage areas, different prescribed doses are delivered, with increased dosage for the target volume and reduced dosage for the organs at risk.

Dosages in the primary nasopharyngeal lesions and subclinical nasopharyngeal lesions are PTV-GTVnx 68–76 Gy/30–33 f, PTV-CTV1 60–64 Gy/30–33 f, and PTV-CTV2 50–54 Gy/30–33 f; 2.00–2.33 Gy per fraction.

Dosages in the cervical lymph nodes and cervical lymphatic drainage areas are PTV-GTVnd 66–70 Gy/30–33 f and PTV-CTV2 50–54 Gy/30–33 f.^19,20

Dose prioritization and acceptance criteria for tumor volumes of organs at risk

There are many important organs in the head and neck, which require precise delineation and dosage. The organs that must be delineated in radiotherapy for NPC include the brain stem, cervical spinal cord, temporal lobe, optic nerve, optic chiasm, pituitary gland, lens, temporomandibular joint, mandible, inner ear, parotid gland, etc. Selectable organs are the eyeball, submandibular gland, oral cavity, tongue, larynx, thyroid, brachial plexus, etc.³⁰

The limited dosage refers to the QUANTEC (2012 standard), which is given according to the specific clinical conditions. The dosages for major vital organs are limited as follows³¹:

Brain stem: D_max ≤ 54 Gy or 1% volume ≤60 Gy

Spinal cord: D_max ≤ 45 Gy

Optic nerve, optic chiasm: D_max ≤ 54 Gy

Lens: D_max ≤ 12 Gy

Temporal lobe: D_max ≤ 60 Gy

Mandible and temporomandibular joint: D_max ≤ 60 Gy

Parotid gland: 50% volume of the whole parotid gland ≤40 Gy; 50% volume of the superficial parotid gland ≤30 Gy

Inner ear: D_max ≤ 40 Gy

It has been reported in the literature that, to ensure the dosage in the target area of tumor invasion and thus to improve the local control rate in IMRT, appropriate adjustment of the limited dosages of organs at risk did not significantly increase the severe radiotherapy complications under the premise of the informed consent of patients. This is worthy of further clinical studies.

Application of special radiotherapies

Special radiotherapies include brachytherapy (BT) and stereotactic radiotherapy. BT, as a supplementary method of external radiation, can effectively reduce the sequelae of radiotherapy caused by external radiation while increasing the radiation dosage in the tumor area and improving the local control rate of the tumor. Stereoscopic radiotherapy achieves high-dose irradiation of the tumor target area through coplanar or non-coplanar multi-field or multi-arc irradiation, while the irradiation volume of normal tissues is significantly reduced, with the high-risk organs fully protected. In newly treated NPC patients, residual lesions after three-dimensional conformal intensity-modulated radiotherapy are given with increased doses of stereotactic radiotherapy, which can achieve better local control and survival rates, but attention should be paid to protecting the carotid sheath to reduce long-term nerve and blood vessel damage after radiotherapy, thus reducing the possibility of severe nasopharyngeal hemorrhage.

Chemotherapy

Chemotherapy is an important treatment option for NPC and it is necessary to develop individualized chemotherapy regimens for patients involving the selection of chemotherapy drugs, chemotherapy timing, chemotherapy course, etc., taking into account factors such as the patient's stage, age, Karnofsky performance status (KPS), complications, drug availability, etc. Cisplatin is still the first choice for chemotherapy, and other drugs include nedaplatin,³² lobaplatin,³³ carboplatin,³⁴ and oxaliplatin.³⁵

Different modes of chemotherapy combined with radiotherapy will significantly affect the benefit of chemotherapy for patients with NPC. For locally advanced NPC, concurrent chemoradiotherapy is the main mode choice. Based on concurrent chemoradiotherapy, combined induction chemotherapy, adjuvant chemotherapy or maintenance chemotherapy will be beneficial to NPC patients, further reducing the risk of distant metastasis and improving the disease prognosis.

Synchronous chemotherapy regimens

Cisplatin (100 mg/m²) every 3 weeks for three cycles or cisplatin (40 mg/m²) weekly during radiotherapy.³⁶ If cisplatin is ineligible or intolerant, e.g. because of hearing impairment, renal insufficiency, and/or neuropathy greater than grade 1, corresponding less toxic alternatives should be selected for clinic treatment, including nedaplatin (category 1B), carboplatin, loplatin, etc.

IC regimens³⁷

Docetaxel, cisplatin, fluorouracil (TPF) (docetaxel 60 mg/m² on day 1, cisplatin 60 mg/m² on day 1, and fluorouracil 600 mg/m² per day from day 1 to day 5, every 3 weeks) (category 1A for EBV-associated disease and category 2A for non-EBV-associated disease),¹⁹ gemcitabine, cisplatin (GP) (gemcitabine 1 g/m² on day 1 and day 8, cisplatin 80 mg/m² on day 1, every 3 weeks) (category 1A),²⁰ and cisplatin, fluorouracil (PF) (cisplatin 80–100 mg/m² on day 1, fluorouracil 800–1000 mg/m² per day from day 1 to day 5, every 3 weeks) (category 2B).³⁸ Other recommended regimens include docetaxel, cisplatin (TP) (docetaxel 75 mg/m² on day 1, cisplatin 75 mg/m² on day 1, every 3 weeks) (category 2B).

Adjuvant chemotherapy regimens

PF (cisplatin 80 mg/m² on day 1, fluorouracil 800 mg/m² per day from day 1 to day 5, every 3 weeks)³⁹ and carboplatin + fluorouracil (category 2B).

Targeted therapy

Targeted therapies are mainly suitable for patients with local advanced NPC or recurrent/metastatic NPC.

EGFR monoclonal antibody combined with concurrent chemoradiotherapy for stage III-IV NPC (category 2B)

For stage III-IV NPC not suitable for chemotherapy, EGFR monoclonal antibody can be used in combination with radiotherapy (category 2B) or combination with induction chemotherapy regimens (category 2B). The addition of epidermal growth factor receptor (EGFR) monoclonal antibody in combination with chemotherapy in patients with recurrent/metastatic NPC may be considered, but further prospective clinical studies are still needed to confirm the efficacy. Representative drugs include (1) cetuximab, administered at 250 mg/m² after a loading dose of 400 mg/m², once a week, and (2) nimotuzumab, recommended at 100 or 200 mg once a week.⁴⁰

Antiangiogenic therapy

Clinical studies have explored the therapeutic effects of antiangiogenic drugs combined with radiotherapy on locally advanced NPC. A previous study has demonstrated that endostar plus radiotherapy has similar efficacy on locally advanced NPC compared with cisplatin combined with radiotherapy, with superior safety and compliance.²³ Multiple clinical studies have also explored the efficacies of endostar in combination with chemotherapy/chemoradiotherapy for patients with recurrent/metastatic NPC, and shown that endostar could improve the prognosis of recurrent metastatic NPC, with tolerable adverse reactions.⁴¹ Other anti-angiogenesis inhibitors (such as bevacizumab, apatinib, and anlotinib) combined with concurrent chemoradiotherapy or radiotherapy have some value in the treatment of locally advanced or recurrent/metastatic NPC. Further in-depth prospective clinical studies are still needed to address these issues.

Nutritional support therapy

According to the patient's condition, treatment timing and appropriate nutritional therapy play key roles in ensuring the success of radiotherapy and chemotherapy, and also affect the patient's recovery and disease prognosis.^42,43 However, no matter what nutritional treatments (either enteral or parenteral nutrition) are adopted, the patient should be evaluated first. To improve the patient's tolerance to radiotherapy and chemotherapy, reduce adverse reactions, and improve quality of life, the nutritional status and energy needs should be formulated and adjusted according to changes in patient weights and related indicators. Recommendations: (1) NPC patients should receive intensive nutritional counseling during radiotherapy and chemotherapy, (2) after radiotherapy or chemotherapy, NPC patients with difficulty in oral feeding could be treated with nasal feeding in the short term, while the percutaneous endoscopic gastrostomy (PEG) is needed in the long term, and (3) NPC patients with gastrointestinal dysfunction should be treated with parenteral nutrition or combined parenteral and enteral nutrition.

DIAGNOSIS AND TREATMENT OF RECURRENT NPC

Recurrent NPC refers to clinical complete elimination of pathologically confirmed NPC after radical radiotherapy, but 6 months after treatment a tumor of the same pathological type appears again in the locoregional area. With the widespread application of IMRT and the development of comprehensive treatment, the local control rate of NPC has been significantly increased, with the local recurrence rate being 10%–15%.

Diagnosis of recurrent NPC

Comprehensive analysis is required based on the patient's medical history, symptoms, signs, EBV-DNA test results, and radiological and histopathological findings. Histopathological examination is the golden standard for the diagnosis of recurrent NPC. For patients with recurrence in the nasopharyngeal cavity, tissue biopsy can be obtained under nasopharyngeal microscope. For patients with suspicious recurrence of the skull base and sinuses, endoscope-guided nasal biopsy can be performed under general anesthesia. For patients with suspicious neck recurrence, fine-needle biopsy cytology of neck mass can be performed. If there is any doubt about the fine-needle biopsy for neck mass, mass resection biopsy can also be performed. For patients with difficult pathological examinations, the MDT can be used for disease diagnosis when the lesions develop progressively.

Treatment strategies for recurrent NPC

It is recommended to use the MDT to obtain a reasonable individualized treatment plan based on the patient's general conditions, including lesion size, location, stage, and interval time of recurrence.

Surgery represents the first choice for local recurrence of NPC meeting the surgical indications, and radiotherapy should be supplemented for patients with positive surgical margins. For those patients who cannot tolerate surgery or with lesions that cannot be removed by surgery, secondary radiotherapy should be performed. Chemotherapy, targeted therapy, and immunotherapy can be considered for those patients who refuse surgery and radiotherapy. For local recurrence and metastatic NPC, radiotherapy for recurrent lesions should only be considered when the metastasis is well controlled. Patients without indications for surgery or radiotherapy should be considered for clinical research.

Radiotherapy

IMRT should be the first choice. The efficacy of the after-loading therapy in the early-staging patients is similar to that of IMRT, but with significantly increased late complications, such as nasopharyngeal necrosis, cranial nerve palsies, hemorrhage, and hearing damage. Whether proton or heavy ion radiotherapy can bring survival benefits needs further study. Target area delineation:

Tumor GTV. GTVnx includes primary tumors visible in imaging and clinical examinations and GTVnd is the metastatic lymph node in the neck.

Clinical CTV. Preventive irradiation should not be considered in the area of lymph node drainage for recurrent NPC, and only the area of the metastatic lymph node should be irradiated for regional recurrence. CTV is recommended for GTVnx with an external expansion of 5–10 mm and regional recurrent lymph nodes.

PTV. Considering the uncertain factors (such as positioning error, systematic error, organ movement, and target area change during irradiation), external expansion of 3–5 mm is recommended. The 60–64 Gy/30–35 f is recommended for PTV. The dose limitation of organs at risk (OAR) represents a difficulty for the re-radiotherapy of recurrent NPC, which depends on the threshold dose of the normal structure and the interval between initial radiotherapy and recurrence. Currently, there is no uniform standard for the dose limitation of OARs and it should be comprehensively considered based on the stage of recurrent tumor, the treatment purpose, and the normal tissue priority. For example, the maximum tolerated dosages for brain stem and spinal cord could reach 40 and 30 Gy during re-radiotherapy, respectively. For other OAR dose limits, the maximum tolerated dose (TD 5/5) minus 30% of the initial exposure dose could be referred to.

Surgery

Nasopharyngeal lesions can be treated by endoscopic NPC resection, which is generally limited to rT1-T2 and some early rT3. Neck surgical methods include radical neck dissection, modified dissection, selective area dissection, and cervical lymphadenectomy.

Chemotherapy

Chemotherapy is the palliative care for advanced locoregional recurrent NPC. For patients with recurrence less than 1 year after the first radiotherapy, chemotherapy can also extend the interval between radiotherapies to protect normal tissues. The clinical value of chemotherapy for recurrent NPC remains to be investigated.

Molecular targeting and immunotherapy

Due to the high expression levels of EGFR and vascular endothelial growth factor receptor (VEGFR) in NPC, the EGFR monoclonal antibodies (Erbitux), VEGFR monoclonal antibodies (Avastin), tyrosine kinase inhibitors (apatinib, anlotinib, etc.), and recombinant human endostatin (endostar) can be used for targeted therapy.

Programmed death-ligand 1 is highly expressed in NPC tissues (up to 90%) that are rich in lymphocytes, indicating that NPC can benefit from immunotherapy. Currently, the immune checkpoint inhibitors include the antibodies against the programmed death factor PD-1/PD-L1 for CD8⁺ T cells and antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Multiple clinical research on immunotherapy for NPC suggests that PD1 inhibitors have certain antitumor effects in recurrent/metastatic NPC, with tolerable adverse reactions. However, the long-term efficacy and safety need to be further verified (category 2B).

DIAGNOSIS AND TREATMENT OF METASTATIC NPC

With the wide application of IMRT, the local control rate of NPC has reached more than 80%, and the distant metastasis has become one of the main factors inducing treatment failure. It is difficult to obtain pathological diagnosis of metastatic lesions, and the accurate diagnosis is difficult to guarantee. Moreover, the disease is heterogeneous, with no standardized treatment strategy, resulting in differential prognosis. Therefore, stratified analysis has been conducted based on the current clinical research and data of metastatic NPC, and a preliminary consensus has been achieved on the diagnosis and treatment strategy norms for metastatic NPC.

Diagnosis of metastatic NPC

NPC can be transferred to multiple organs of the body through blood circulation. Generally, patients with distant metastases account for about 10% of initially treated cases. Among patients for whom no metastases have been detected at initial treatment, about 15% will still suffer from distant metastases after treatment. Common metastatic sites include the bone, lung, and liver. Since it is difficult to obtain the pathological diagnosis of metastases, it is necessary to make judgments based on the imaging examination results, especially functional imaging (such as bone ECT, PET/CT) and EBV-DNA.

Treatment of metastatic NPC

Systemic treatment (four to six courses) represents the main treatment approach of metastatic NPC. Based on the idea of systemic therapy (consisting of chemotherapy, targeted therapy, immunotherapy, etc.), for patients with good tumor control and prognosis, it is recommended that local treatment methods (such as surgery, radiotherapy, and interventional therapy) are applied to simultaneously treat the primary lesions and metastases (patients with metastasis before initial treatment) to obtain long-term tumor control.

Management of primary lesions

Many retrospective clinical studies have shown that systemic therapy combined with local radiotherapy could significantly improve the prognosis of patients with metastatic NPC, especially patients with single or relatively few metastases (some cases could even achieve radical cure). It is suggested that deciding whether or not to give local radiotherapy depends on the tumor's responsiveness to chemotherapy, which can effectively screen out the most suitable patients and avoid unprofitable local treatments.

Treatment of metastases

The types of metastases in patients with NPC include single metastasis, oligometastasis, and multiple metastases, with different treatment methods and prognosis. Different types of metastases need to be subjected to different treatments. Oligometastasis, a transitional state between local invasion and extensive metastasis, has relatively weak metastatic ability, with limited metastasis location and numbers (usually fewer than five metastases). When oligometastatic lesions are actively treated, some patients can be cured by the radical treatment of primary NPC. Due to the large number and wide distribution of multiple metastases, local treatment is difficult to perform and the survival rate for patients with metastases is low. At present, there is still no clear evidence that the active treatment of metastases can bring survival benefit. It should be handled according to the clinical situation. Palliative treatment is recommended for some patients with symptoms.

DIAGNOSIS AND TREATMENT OF SPECIAL TYPES OF NPC

NPC pathological types mainly include adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystadenocarcinoma. Biopsies obtained from nasopharyngeal tissue should be sufficient for pathological tests (e.g. hematoxylin and eosin staining and immunochemistry staining). If neck lymph node resection biopsy is performed, complete removal of the lymph node is recommended. It has been reported that neck lymph node resection or needle biopsy will increase distant metastases (up to 20%), with a significant impact on the disease prognosis.

Nasopharyngeal salivary gland adenocarcinoma

Nasopharyngeal salivary gland adenocarcinoma originates from the submucosal proper small salivary glands, including nasopharyngeal adenoid cystadenocarcinoma and nasopharyngeal mucoepidermoid carcinoma. These two kinds of tumors have different clinical characteristics and low incidence rates. Currently, there is still no standard treatment model. Nasopharyngeal salivary gland adenocarcinoma is not sensitive to radiotherapy, so surgery is the first choice for complete lesion resection. However, due to the complex structure around the nasopharynx (even in the early stage), thorough resection cannot be guaranteed. Radiotherapy for nasopharynx salivary gland adenocarcinoma still achieves the same survival rate as other nasopharynx cancer types.⁴⁸ Currently, there are still no recommended chemotherapy regimens, targeted therapy drugs, and/or immunotherapy drugs for nasopharyngeal salivary gland adenocarcinoma. Concurrent chemoradiotherapy with platinum-containing drugs can be used as a feasible treatment for patients with salivary gland adenocarcinoma who cannot tolerate surgery.

Nasopharyngeal adenocarcinoma

Nasopharyngeal adenocarcinoma originates from the surface of the mucosal epithelium in the pharynx, and is an extremely rare malignant tumor. The prevalence age is 46–50 years old, and the tumor mostly occurs in males. The tumor is mainly characterized by slow growth, long course, easy recurrence, and blood metastasis. Pathological types are more common in papillary adenocarcinoma, also known as low-grade and thyroid-like papillary adenocarcinoma. Currently, the comprehensive treatment of nasopharyngeal adenocarcinoma is based on local surgical resection. For lesions that cannot be completely resected, radiotherapy can be adjuvanted to reduce recurrence. There are few reports in the literature concerning the role of chemotherapy in the treatment of nasopharyngeal adenocarcinoma. Commonly used drugs for nasopharyngeal adenocarcinoma include cisplatin, adriamycin, 5-fluorouracil, cyclophosphamide, bleomycin, and docetaxel. However, none of these has satisfactory effect. Chemotherapy has often been applied in combination with radiotherapy. Currently, there are still no recommended targeted therapy drugs and/or immunotherapy drugs for nasopharyngeal adenocarcinoma.

NPC in adolescents and children

NPC has been rarely seen in adolescents and children, with an incidence rate of <5% as childhood malignant tumors. The incidence rate for boys is higher than that of girls, and the onset age is often less than 18 years old.⁴⁹ Genetic susceptibility is the main factor causing NPC in children. Although most children with NPC are locally advanced, the disease prognosis is better than that of adults. The treatment principle is based on comprehensive treatment with radiotherapy as the mainstay, and radiotherapy alone is recommended for early patients. Moreover, IMRT is recommended. The target delineation range is the same as that of adult NPC. For radiation doses, a dose of 50–72 Gy is appropriate for children over 10 years old, while for those under 10 years old the total dose should be reduced by 5%–10%. Children with NPC are also sensitive to chemotherapy, and a comprehensive treatment model of radiotherapy and chemotherapy is recommended for patients with locally advanced lesions, including induction chemotherapy and concurrent chemotherapy, with the choice of drugs referring to adult NPC patients. There is no satisfactory treatment plan for recurrent or metastatic NPC in children. Exploring novel high-efficiency and low-toxicity chemotherapy and/or other therapies is one of the important directions for current research.

Nasopharyngeal cancer during pregnancy

For patients with NPC during pregnancy, it is recommended that women in the second trimester should receive radiotherapy after artificial abortion, while women in late pregnancy should receive radiation therapy after induction of labor or cesarean section. For these patients, IMRT would be recommended. The commonly used fractional radiotherapy is five times a week, once per day at 2 Gy each time, with a dose of 65–75 Gy.⁵⁰ It is suggested that women of childbearing age should give birth 2 years after radiotherapy to reduce the impact of radiotherapy on the fetus. Chemotherapy should be carefully considered for NPC cases during pregnancy, and cisplatin and fluorouracil should be avoided in the early pregnancy. Currently, there are no recommended targeted therapy drugs and/or immunotherapy drugs for NPC during pregnancy.

COMMON COMPLICATIONS OF RADIOTHERAPY AND MANAGEMENT Complications and management of radiotherapy

The common complications of radiotherapy for NPC include acute radiation mucositis, radiation dermatitis, radiation salivary gland injury, acute ear injury, and radiation brain necrosis. The Radiation Therapy Oncology Group (RTOG) damage grading standard is shown in Appendix 3.

Acute radioactive mucositis

Acute radioactive mucositis usually occurs at 1–2 weeks after radiotherapy (cumulative radiation dose up to 10–20 Gy), often accompanied by mild taste change, xerostomia, and viscous saliva, and gradually aggravated, which can last through the whole radiotherapy process and gradually recover at 1–3 weeks after radiotherapy. Generally, local or systemic symptomatic drug treatment (such as amifotin^51,52) and traditional Chinese medicine also have good effects.

Acute radioactive dermatitis

Acute radiation dermatitis usually begins to appear 2–3 weeks after starting radiotherapy and continues until 2–4 weeks after treatment. Treatment mainly focuses on prevention and symptomatic treatment. Dry dermatitis needs no special treatment. When large moist desquamation occurs, attention should be paid to keeping the skin clean and dry, avoiding friction, preventing infection, appropriately giving drugs to promote epidermal growth, and radiotherapy interruption if necessary.⁵³

Acute radioactive salivary gland injury Acute radioactive parotitis

Acute radioactive parotitis usually appears during the first 1–3 days after radiotherapy, and often manifests as swelling and pain in one or both parotid glands. In severe cases, the skin turns red, accompanied by increased temperature. Generally, no special treatment can be helpful except for self-healing. If there is fever and suspected secondary infection, special oral care and anti-infection analgesic treatment should be given, and radiotherapy should be suspended if necessary.

Radiation xerostomia

Radiation salivary gland injury is the direct cause of radiation xerostomia. Studies have shown that the probability of significant xerostomia symptoms in patients with NPC after intensity-modulated radiation therapy might be as high as 30%. Prevention is key to reduce radiation xerostomia, such as improving the accuracy of radiotherapy, IMRT, and image-guided radiotherapy. Traditional Chinese medicine has great potential for treating radiation xerostomia.⁵⁴

Acute radiation ear injury

Acute radiation ear injury usually presents as tinnitus and hearing loss. It is a common effect due to toxicity during radiotherapy, which generally needs no special treatment. If eardrum perforation and fluid flow occur, local cleaning and anti-inflammatory treatment should be carried out.⁵⁵

Radiation encephalopathy

Radiation encephalopathy has a long incubation period and is most common in bilateral temporal lobes. Clinically, mild cases have no obvious symptoms, while severe cases might result in death.⁵⁶ At present there is no specific medicine for clinical treatment, just effective prevention. For T4 stage NPC with obvious intracranial invasion, induction chemotherapy is recommended to minimize the tumor volume and adaptive radiotherapy techniques (such as multiple plans) should be adopted to minimize the dose and volume of exposure to the temporal lobe and brain stem to prevent the occurrence of radioactive brain necrosis. The traditional treatment strategy for radiation cerebral necrosis is the administration of large doses of vitamins, vasodilators, neurotrophic drugs, and glucocorticoids.⁵⁷ Bevacizumab has been shown in two prospective clinical studies to improve the edema caused by radioactive brain injury, with higher therapeutic efficiency than traditional hormone therapy.^58,59 Moreover, nerve growth factor combined with intermittent glucocorticoids can repair 20% of temporal lobe injuries.^57,60

NPC WHOLE-PROCESS MANAGEMENT: BEFORE, DURING, AND AFTER TREATMENT Management before NPC treatment

The patient's status should be fully assessed before treatment and the following tests should be performed according to clinical indications: KPS score, Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS) score, depression screening, dental, oral repair, and evaluation of the risk of xerostomia and salivary gland dysfunction resulting from head and neck radiation therapy, including radiation osteonecrosis, audiogram testing, ophthalmological and endocrine assessment (specialist assessment recommended), smoking cessation management, fertility/reproductive counselling, and assessment and management of nutrition, speech and swallowing function, and oral mucosal pain.

Management during the treatment of NPC

Patients may show adverse reactions to varying degrees due to chemoradiotherapy and immunotherapy during treatment. During radiotherapy, the skin and soft tissue should be protected, keeping the mouth clean to promote healing of radiation-induced oral mocositis. Oral candidiasis and treatment should be evaluated according to clinical instructions. Moreover, attention should be paid to nasal protection/nasopharyngeal cavity cleaning, as well as nutrition status. Effective intervention should be carried out in time if necessary. Furthermore, attention should be paid to the adverse reactions caused by chemotherapy, including bone marrow suppression, nausea, vomiting, diarrhea, liver and kidney function damage, neurotoxicity and oral mucosal damage. During immunotherapy, immune-related adverse events should be noted.

Management of NPC after treatment

Local or regional residues or distant metastasis are suspected after treatment and should be reviewed at least once a month after treatment. In the absence of the above situations, patients should be reviewed once a month after treatment, then once every 3 months (with a maximum of no more than 4 months) within 1–3 years after primary treatment, once every 4–5 months (with a maximum of no more than 6 months) within 3–5 years, and once a year after 5 years. It is recommended that the Response Evaluation Criteria In Solid Tumors version 1.1 is used for efficacy evaluation. Where possible, assessments should be carried out by the same evaluator to ensure consistency between visits. If disease progression is suspected, an imaging scan should be conducted.

Follow-up after treatment should include detailed physical examination, hematologic examination, complete head and neck imaging examination, indirect nasopharyngoscopy or fiberoptic nasopharyngoscopy, plain or enhanced chest CT, ultrasound for abdomen and bone ECT, and EBV DNA monitoring. If radiotherapy is given to the neck region, thyroid stimulating hormone should be reviewed every 6–12 months.

After radiotherapy, it is still necessary to protect the skin and soft tissue in the radiation field and exercises of mouth opening and neck turning should be continued and strengthened, keeping the oral cavity clean. Moreover, attention should be paid to the cleaning and protection of the nasal cavity/nasopharyngeal cavity. Dental assessment of oral and intraoral radiotherapy sites, and assessment of speech, hearing, swallowing functions, nutrition, and psychological status, should be performed regularly.

CONFLICT OF INTEREST

The authors declare no conflict of interest in this work.

Expert group of Chinese guidelines for radiotherapy of NPC (2020 Edition).

Members of the Advisory Panel (in alphabetical order by surname): Taixiang Lu (Sun Yat-Sen University Cancer Center), Jinyi Lang (Sichuan Cancer Hospital), and Guozhen Xu (Chinese Academy of Medical Science Cancer Hospital).

Group Leaders: Rensheng Wang (The First Affiliated Hospital of Guangxi Medical University), Jianji Pan (Fujian Cancer Hospital), Jun Ma (Sun Yat-Sen University Cancer Center), Yunbin Chen (Fujian Cancer Hospital), and Chong Zhao (Sun Yat-Sen University Cancer Center).

Deputy Group Leaders (in alphabetical order by surname): Xiaoshen Wang (Fudan University Shanghai Cancer Center), Liangfang Shen (Xiangya Hospital of Central South University), Xia He (Jiangsu Cancer Hospital), Runye Wu (Chinese Academy of Medical Science Cancer Hospital), Jingao Li (Jiangxi Cancer Hospital), Kunyu Yang (Union Hospital of Huazhong University of Science and Technology), Jingfeng Zong (Fujian Cancer Hospital), Shaojun Lin (Fujian Cancer Hospital), Feng Jin (Affiliated Hospital of Guizhou Medical University), Heming Lu (the People's Hospital of Guangxi Zhuang Autonomous Region), Xiaozhong Chen (Zhejiang Cancer Hospital), Man Hu (Shandong Cancer Hospital and Institute), and Haixin Huang (Liuzhou Workers’ Hospital).

Members of the Writing Expert Group (in alphabetical order by surname): Daiyuan Ma (Affiliated Hospital of North Sichuan Medical College), Xiaomin Ou (Fudan University Shanghai Cancer Center), Yanhong Fang (Fujian Cancer Hospital), Ruozheng Wang (Affiliated Tumor Hospital of Xinjiang Medical University), Zhe Wang (Affiliated Zhongshan Hospital of Dalian University), Jingbo Wang (Chinese Academy of Medical Science Cancer Hospital), Lan Wang (The Fourth Hospital of Hebei Medical University), Wenqi Liu (The Second Affiliated Hospital of Guangxi Medical University), Lei Liu (West China Hospital of Sichuan University), Yan Sun (Beijing Cancer Hospital), Qiong Wu (The First Affiliated Hospital of Soochow University), Xinmao Song (Eye & ENT Hospital of Fudan University), Ximei Zhang (Tianjin Medical University Cancer Hospital), Yong Zhang (The First Affiliated Hospital of Guangxi Medical University), Xiaojing Du (Sun Yat-Sen University Cancer Center), Fujun Yang (Shandong Weihai Municipal Hospital), Erdong Shen (The First People's Hospital of Yueyang City), Youping Xiao (Fujian Cancer Hospital), Shaomin Lin (Hainan General Hospital), Zhixiong Lin (Cancer Hospital of Shantou University Medical College), Xi Lin (Fujian Cancer Hospital), Liqing Su (Fujian Cancer Hospital), Hekun Jin (Hunan Provincial Cancer Hospital), Ying Lu (Liuzhou Workers' Hospital), Shaoqing Chen (The First Affiliated Hospital of Nanchang University), Chuanben Chen (Fujian Cancer Hospital), Yong Chen (The First Affiliated Hospital of Sun Yat-sen University), Feng Jiang (Zhejiang Cancer Hospital), Guangyuan Hu (Tongji Hospital of Huazhong University of Science and Technology), Qiaoying Hu (Cancer Hospital affiliated to University of Chinese Academy of Sciences), Xiaoxia Gou (Affiliated Cancer Hospital of Zunyi Medical University), Yahua Zhong (Zhongnan Hospital of Wuhan University), Jiyong Qin (Yunnan Cancer Hospital), Hao Gu (The First Affiliated Hospital of Zhengzhou University), Jin Gao (Anhui Cancer Hospital), Min Kang (The First Affiliated Hospital of Guangxi Medical University), Yuandong Cao (Jiangsu People's Hospital), Xiaochang Gong (Jiangxi Cancer Hospital), Fei Han (Sun Yat-Sen University Cancer Center), Daoliang Bao(Fujian Cancer Hospital), and Jian Zang (Xijing Hospital of Air Force Military Medical University).

Min Kang (The First Affiliated Hospital of Guangxi Medical University).

Appendix: UICC/AJCC Staging System for NPC (8th Edition, 2017)

Primary Tumor (T)

TX: Primary tumor cannot be assessed

T0: No tumor identified, but EBV-positive cervical node(s) involvement

Tis: Carcinoma in situ

T1: Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement

T2: Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, and prevertebral muscles)

T3: Tumor with infiltration of bony structures at skull base, cervical vertebra, prerygoid structures, and/or paranasal sinuses

T4: Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed

N0: No regional lymph node metastasis

N1: Unilateral metastasis in cervical lymph node(s) and/or unilateral or bilateral metastasis in retropharyngeal lymph node(s), 6 cm or smaller in the greatest dimension, above the caudal border of cricoid cartilage

N2: Bilateral metastasis in cervical lymph node(s), 6 cm or smaller in the greatest dimension, above the caudal border of cricoid cartilage

N3: Unilateral or bilateral metastasis in cervical lymph node(s), larger than 6 cm in the greatest dimension, and/or extension below the caudal border of cricoid cartilage

Distant metastasis (M)

M0: No distant metastasis

M1: Distant metastasis

Clinical stage

Stage 0: TisN0M0

Stage I: T1N0M0

Stage II: T0-1N1M0, T2N0-1M0

Stage III: T0-2N2M0, T3N0-2M0

Stage IVA: T0-3N3M0, T4N0-3M0

Stage IVB: Any T; any N and M1

I APPENDIXMRI diagnosis of NPC Section 1: MRI examination technique for NPC A.1 Preparation before inspection

   

• 1.1Magnetic resonance examination is prohibited for patients with contraindications (such as pacemakers, artificial metal heart valves, aneurysm clips, claustrophobia, etc.).
• 1.2Before the examination, the patient should change clothes, put on the examination gown, and remove metal foreign bodies (such as artificial eyes, dentures, wigs, prostheses, etc.).
• 1.3The patient should open the venous access and place the vein indwelling needle.
• 1.4After the patient enters the computer room, hearing protection should be used, such as ear plugging with cotton balls or wearing earplugs.

A.2 Scanning coil selection

Clinical staging of NPC requires MRI scanning of the nasopharyngeal skull base and neck. The HEAD NECK joint coil is usually used to ensure that the scanning range covers the skull base and the entire neck to obtain good signals, especially for the skull base and lower neck.

A.3 Position and positioning line

The patient lies in the supine position. The shoulders are close to the head and neck coil, placed in the middle. The head should not be rotated, and the head pads are fixed on both sides, to match the positioning of the radiotherapy simulated CT. The nose line is perpendicular to the bed surface. The positioning center is located at the nose tip (Fig. 1.1). When the laser light passes across the patient's eyes, they should be closed for protection.

FIGURE 1.1. 16NV_HEAD NECK joint coil and patient scanning position

A.4 Scanning sequence specification

• 4.1Positioning 3-plane localizer scan (3-pl loc) (axial, coronal and sagittal) scan. To ensure coverage of the nasopharyngeal skull base and neck, a larger field of view is usually used. The nasopharyngeal skull base and neck should be located in the center of the coil, and the imaging signals should be well matched with the coil position. The numbers of coronal and sagittal slices of the positioning image should be sufficient to ensure the axial positioning range (Figure 1.2).
• 4.2The plain scan sequence. Axial and sagittal T1WI sequence, axial and coronal T2WI plus fat suppression sequences, and axial DWI sequence (b value of 0 and 600–1000 s/mm²).
• 4.2.1Axial T2WI sequence. The axial scan position is performed on the sagittal plane of the image, and the numbers of slices and scan range are determined to ensure that the scan is in the positive axial position and is consistent with the simulated CT positioning of NPC radiotherapy, generally no angle. It is usually positioned on a sagittal image, centered on the anterior margin of the third cervical vertebra, and scanned from the middle pole of the temporal lobe to the level of the aortic arch (Figure 1.3).

FIGURE 1.2. MRI scan of nasopharyngeal skull base and neck for positioning 3-pl loc (sagittal, coronal, and axial)

FIGURE 1.3. Scanning positioning, layer number, and scanning range of axial image

Notes: Upper and lower saturation bands can be added appropriately to reduce the vascular pulsation artifacts. Considering the rich subcutaneous fat in the neck, to facilitate the observation of the perinasopharyngeal tissue space and the details of bone lesions in the skull base and neck lymph nodes, the adipose tissue signal in the head and neck should be eliminated with fat suppression technology to avoid missed diagnosis caused by high-signal adipose tissue covering the high-signal lesions on T2WI. Due to the high resolution, the fat suppression technique facilitates the observation of small lesions in the nasopharyngeal mucosa, interstitial spaces, and skull base bones. It is also helpful to observe whether the neck lymph node capsule is intact.

• 4.2.2Axial T1WI sequence. The scanning position, layer number, and scanning range of the sequence should be consistent with that of the axial T2WI sequence, which could contribute to synchronously observing the signal characteristics of the lesions in different sequences. Lesions of skull base are mostly hypointense while fat appears hyperintense in T1WI sequences without fat suppression. So tumor involvement of skull base can be clearly visualized and distinguished in T1WI sequences without fat suppression.

Notes: As with the T2WI sequence, the upper and lower saturation bands can be added appropriately to reduce the vascular pulsation artifacts, which extends the scan time. Since the T1WI sequence without fat pressure can clearly show the normal anatomical structure of the nasopharyngeal skull base and neck, it is helpful for judgement of the lesions and observation of the skull base bone lesions.

• 4.2.3Coronal T2WI sequence. During MRI scanning, a localizer MRI scan was acquired for localizing coronal MR images which was cencered on the leading edge of 3th cervical vertebra (C3). The scanning baseline should be parallel to the anterior edge of the third cervical vertebra. Special physiological curvatures are shown in the nasopharyngeal neck (including the cavernous sinus of the skull base, nasopharynx, and anterior cervical lymph nodes), and the scanning range is from the middle of the temporal lobe to the level of the aortic arch (Figure 1.4).

FIGURE 1.4. Scanning positioning and scanning range of coronal image

Notes: When positioning, the front and rear position and rotation angle can be adjusted on the axis positioning image. Appropriate addition of upper and lower saturation bands can reduce artifacts due to respiratory movement or vascular pulsation. Frequency coding is generally placed on the left and right sides, which can further reduce the jugular arteriovenous flow and/or pulsation artifacts. The coronal T2WI sequence can not only show the invasion of the nasopharyngeal lesions to the skull base and intracranial intuitively, but also clearly show the invasion of the lesion down to the supercavity and the scope of invasion of the contralateral structure. More importantly, bilateral cervical lymph nodes can be observed on a large scale. For the comprehensive observation of lymph nodes in both necks, if necessary, scanning oblique coronal or oblique sagittal T2WI sequence can be added to judge the violation of the masticatory muscle space.

• 4.2.4Sagittal T1WI sequence. Scanning and positioning of sagittal images are performed on the coronal image of the positioning image, with the median sagittal line as the baseline. The scanning range is from the mid-temporal lobe to the level of the aortic arch (Figure 1.5).

FIGURE 1.5. Scanning positioning and scanning range of sagittal image

Notes: When positioning, it is necessary to adjust the left and right ranges, and the rotation angle on the horizontal axis positioning image. Generally, frequency coding is placed before and after, which can reduce the jugular arteriovenous flow and/or pulsation artifacts.

• 4.2.5Axial DWI sequence. An echo planar imaging sequence based on short time of inversion recovery can be used. The scanning position, number of layers, and scanning range are consistent with the axial T2WI sequence. The b value is selected as 0 and 600–1000 s/mm². The upper and lower saturation bands can be appropriately added to reduce the vascular pulsation artifacts.

• 4.3 Enhanced scan sequence. Fat suppression technology must be used. Clinically, the T1WI sequence is generally used for axial, coronal, and sagittal enhanced scanning. The scan positioning, number of layers, and scan range are consistent with the sequence of the plain scan.

Notes: Due to the complexity of the skull base and neck anatomy, the scanning requirements are relatively high. It is recommended that upper and lower saturation bands are added to reduce the enhanced vascular pulsation artifacts. At the same time, shimming needs to be added, and the shimming range should not include air.

Because the uniformity of the neck magnetic field is affected by the anatomical structure, fat suppression is often uneven during T1WI large-scale scanning. If a fat suppression enhanced scan is performed, local shimming needs to be added, centering on the lesion. If the fat suppression effect is not satisfactory during T1WI scanning, it is recommended that the T1WI IDEAL sequence is used for scanning enhancement, with a relatively uniform fat suppression. The frequency encoding direction is generally placed in a direction prone to motion artifacts.

• 4.4 Contrast agent usage plan. Gadolinium contrast agent is injected with the intravenous needle. The dosage is 0.1–0.2 mmol/kg, with an injection rate of 1–2 ml/s. After the contrast agent injection, an appropriate amount of saline should be used to flush the tube to ensure that all the contrast agent in the catheter is injected into the vein.
• 4.5 Enhanced scan phase. After enhanced scanning, various tissue has different T1 relaxation times resulting in different signal intensities among tumor tissue, normal nasopharyngeal tissue, and lymph node tissue. And the difference of relaxation rate among the three tissue changes over time. Because the enhanced scanning time changes, it is helpful to choose a reasonable enhanced scanning to show the structures of the meninges, cranial nerve sheath, and lymph node capsule. However, it is still necessary to identify a more reasonable enhanced scanning phase (Figure 1.6).
• 4.6 Application of water-fat separation imaging technology in NPC staging (MRI-Dixon)

FIGURE 1.6. Enhanced scanning images of NPC in axial, coronal, and sagittal (from a to c) positions

The in-phase and anti-phase images produced by chemical shift imaging can be used to indirectly calculate the images of separate water and fat signals, that is, water–fat separation imaging, which has gradually replaced fat pressure imaging as a clinically used advanced magnetic resonance imaging diagnostic method. Water–fat separation imaging has unique value for clear visualization of the lesion and surrounding tissues under fat suppression conditions and fat disease diagnosis. This method is called the Dixon method and can be applied to the spoiled gradient echoes sequence (GRE) T1WI sequence, spin echo (SE) sequence, or fast spin echo (FSE) sequence.

The advantages of water–fat separation imaging technology in the NPC staging are as follows:

(1) Four images can be obtained at one time, namely water, fat, in-phase, and anti-phase images, which can provide richer diagnostic information for the identification and composition of lesions.

(2) Compared with traditional reversal recovery or fat-saturated fat pressing technology, water–fat separation technology, which is insensitive to the inhomogeneity of B0 and radiofrequency, does not affect the longitudinal magnetization, making it effective in low-field magnetic resonance to obtain high-quality compressed fat images.

(3) This technique can better display areas that are difficult for traditional liposuction techniques. For example, it can improve the detailed display of the lymph nodes in the meninges, parotid area, floor of the mouth, and cervical-thoracic junction, which have greater clinical significance for NPC staging.

Section 2: Normal MRI of nasopharynx

On the MR images, the signal features of the normal anatomy of the nasopharynx include (1) gas, low signal intensity on all sequences, (2) muscle, isointensity on T1WI and slightly low signal intensity on T2WI, (3) bone, low signal intensity for bone cortex on both T1WI and T2WI, while the cancellous bone showing high signal intensity due to the fat content, (4) fat, high signal intensity on T1WI and T2WI, low signal intensity on fat-suppression sequence, and (5) blood vessel, empty signal on weighted SE sequence and significantly high signal intensity on T1WI enhancement scanning.

A.1 Fascial space of suprahyoid neck A.1.1 Pharyngeal mucosal space

The pharyngeal mucosal space (PMS) is surrounded by the middle layer of the deep cervical fascia (DCF). The middle layer of the DCF surrounds the lateral and posterior margins of the pharyngeal basicranial fascia in the nasopharynx. In the oropharynx, the DCF is located in the deep surface of the superior and middle pharyngeal constrictor. In the laryngopharynx, the DCF is located in the deep surface of the inferior pharyngeal constrictors. The PMS anterior is the airway, the posterior is the posterior pharyngeal space, and the lateral is the parapharyngeal space. The structures in the space include the pharyngeal mucosa, lymphoid tissue, minor salivary glands, pharyngobasilar fascia, constrictor naris, salpingopharyngeus, petrostaphylinus, torus tubarius, and ostium pharyngeum tubae auditivae.

A.1.2 Retropharyngeal space

The retropharyngeal space (RS) is located behind the PMS, medial to the bilateral parapharyngeal space, and anterior to the danger space. The RS extends from the skull base to the third thoracic vertebra level of the mediastinal. The anterior wall is the middle layer of the DCF, and the posterior and lateral walls are the alar fascia. This space contains fat and the retropharyngeal lymph nodes. It should be noted that the retropharyngeal lymph nodes are only distributed in the postpharyngeal space above the hyoid level, and there are no lymph nodes below the hyoid level.

A.1.3 Parapharyngeal space

The parapharyngeal space (PPS) is like an inverted cone, bottom hole to the skull base, close to the jugular vein, pointing toward the thyrohyal, inward to the intermediate layer of the DCF that surrounds the PMS, outward to the superficial layer of the DCF that covers the masticator space and parotid space, posterior to the deep layer of the DCF and the anterior part of the carotid sheath that forms the anterolateral margin of the RS. The space includes fat, the internal maxillary artery, the ascending pharyngeal artery, ectopic minor salivary glands, without lymph nodes, mucosas, muscles, and bones.

A.1.4 Carotid space

The carotid space is composed of the superficial, middle and deep layers of the DCF. It runs from the skull base to the arch of the aorta. The main structures in the space are the internal carotid artery, the common carotid artery, the internal jugular vein, and the nineth to twelfth cranial nerves. The lymphatic chain of the internal jugular vein is closely connected to the carotid space. The sympathetic plexus is located between the carotid space and the retropharyngeal space.

A.1.5 Masticator space

The masticator space (MS) is surrounded by the superficial layer of the DCF that divides on the lower margin of the mandible. The facies interna of the superficial layer of the DCF is covered by the medial pterygoid, embedded in the skull base and attaching to the lower part of the foramen ovale. The outer layer covers the masseter muscle, extends into the zygomatic arch, and finally attaches to the skull along the cranial margin of the temporalis muscle (TM). The MS is divided into the upper and lower parts by the zygomatic arch. The MS above the zygomatic arch contains only the temporalis muscle. The MS below the zygomatic arch mainly contains the medial pterygoid (MP), lateral pterygoid (LP), masseter muscle (MM), mandibular nerve, mandibular ramus and the posterior part of the mandible body. The MP is located in the medial inferior part of the MS, with deep and shallow heads. The deep head is from the lateral pterygoid plate and the pyramida process of the palatine bone. The shallow head is from the pyramida process of the palatine bone and maxillary tubercle. The muscle fibers oblique outward and downward, ending at the pterygoid tubercles of the mandibular angle. The LP is located above the MP, with both upper and lower heads. The upper head arises from the facies infratemporalis and the infratemporal crest of the greater wing of sphenoid bone. The lower head arises from the facies lateralis of the lateral pterygoid plate, runs posterolaterally, and ends at the condyle of the articular wing muscle fossa of the condylar neck. The triangular clearance between the anterolateral of the LP, the medial margin of the ascending ramus of the mandible, and the posterior wall of the maxillary sinus is called the anterior pterygium. The TM arises from the temporal fossa and forms a fan-shaped flat muscle, passing downwards through the deep surface of the zygomatic arch and ending at the coronoid process mandible. The MM arises from the lower margin and inner surface of the zygomatic arch, and extends posteroinferilly to the exterior of the mandibular ramus, ending at the exterior of the mandibular ramus and the masseter tuberosity. The MP, LP, TM, and MM are all innervated by the motor branches of the mandibular nerve.

A.1.6 Parotid space

The parotid space is located posterolaterally in the masticator space, which is formed by the superficial layer of the DCF surrounding the parotid gland. The parotid space contains the parotid, facial nerve, retromandibular vein, external carotid artery and intraglandular parotid lymph nodes. Anatomically, there may be as many as 20 lymph nodes in the parotid gland.

A.1.7 Perivertebral space

The perivertebral space is formed by the DCF surrounding the cervical, thoracic, and peripheral muscles, starting from the skull base and descending to the level of the fourth thoracic vertebra. The perivertebral space can be further divided into the anterior and posterior paravertebral parts. The anterior vertebral muscle includes the longus capitis, longus colli, annuens, and rectus capitis lateralis. The longus capitis is located anterolateral to the longus colli and posterolateral to the annuens and rectus capitis lateralis.

A.1.8 Buccal space

The medial side of the buccal space is the buccinator and the maxillary alveolar crest, and the posterolateral side is the masticator space, which is separated from the subcutaneous tissue forward by the facial expression muscle. The buccal space is mainly composed of fat, but also contains minor salivary glands, parotid ducts, lymph nodes, facial veins, the cheek artery, the buccal branch of the facial nerve, and the buccal branch of the mandible nerve (Fig. 2-1).

FIGURE 2.1. (A) Axial view of T1WI imaging: 1, buccal space; 2, masticator space (fine line); 3, parapharyngeal space; 4, parotid space (fine line); 5, carotid space (fine line); 6, retropharyngeal space. (B) Axial view of T1WI imaging: 1, masseter muscle; 2, temporalis muscle; 3, medial pterygoid; 4, lateral pterygoid; 5, maxillary bone; 6, pterygoid process; 7, mandibular ramus. (C) Coronal view of T2WI imaging: 1, temporalis muscle; 2, lateral pterygoid; 3, parotid gland; 4, medial pterygoid; 5, masseter muscle; 6, pharyngeal mucosal space (fine line); 7, parapharyngeal space (fine line). (D) Axial view of T1WI imaging: *, prevertebral muscle

A.2 Nasopharynx, oropharynx, and laryngopharynx

The pharynx is a funnel-shaped muscular tube that is wide above and narrow below, and a little flat in the anteroposterior axes. Its upper end is attached to the skull base, and the lower end is flat with the cricoid arch (i.e., the inferior margin of the sixth cervical vertebra). The pharynx connects to the esophagus downward, with a total length of about 12 cm. The pharynx is the common channel between the respiratory and digestive tracts. From top to bottom, the pharynx is divided into the nasopharynx, oropharynx, and laryngopharynx by the free edge of the velum palatinum (i.e., the inferior margin of the second cervical vertebra) and the superior border of the epiglottis (i.e., the inferior margin of the third cervical vertebra).

The nasopharynx connects forward to the nasal cavity and downward to the oropharynx. The boundary between the nasopharynx and the oropharynx is the free edge of the velum palatinum. The lateral and posterior boundary is the pharyngobasilar fascia. The posterior external third of the auditory tube is the bony part, while the anterior internal two-thirds is the cartilage. The cartilaginous inner part of the auditory tube forms a protuberance known as the tubal torus. There is a pit between the posterior upper part of the auditory tube and the posterior wall of the pharynx, which is the most common site for NPC.

The pharyngobasilar fascia at the base of the pharynx is dense connective tissue in the posterior-lateral wall of the nasopharynx, which presents the low signal intensity on both T1WI and T2WI MRI. The pharyngobasilar fascia arises from the posterior margin of the medial pterygoid plate, travels backwards between the staphylinus externus and levator veli palatini, then turns inward at the anterior of the carotid foramen and passes through the posterior pharyngeal wall and the anterior of the vertebral anterior muscle. Although the pharyngobasilar fascia is an important barrier to prevent tumor invasion, it has two weak spots: (1) the tumor can spread to the cerebral by destroying the structures surrounding the lacerated foramen and (2) in the upper part of the pharyngobasilar fascia, adjacent to the pharyngeal recess, there is a Morgagni sinus opening into the nasopharyngeal cavity through which the tumor may invade the parapharyngeal space (Figure 2.2).

FIGURE 2.2. (A) Sagittal view of T1WI imaging: 1, nasopharynx; 2, oropharynx; 3, laryngopharynx. (B) Axial view of T2WI-STIR imaging: 1, nasopharynx; 2, pharyngeal recess. (C) Axial view of T2WI imaging: 1, medial pterygoid; 2, lateral pterygoid; 3, torus tubarius; 4, vertebral anterior muscle; 5, staphylinus externus; 6, levator veli palatini. (D) Schematic diagram of the pharyngobasilar fascia (fine line)

A.3 Nasal cavity and paranasal sinus

The part of the nasal cavity that connects forward to the outside is called the nostril, and the area leading backwards to the nasopharynx is called the choana. The paranasal sinus is an air-filled cavity inside the skull that surrounds the nasal cavity, connecting with the nasal cavity through the natural sinus. There are four pairs of paranasal sinus: frontal, ethmoid, sphenoid, and maxillary. The sphenoid sinus resides in the sphenoid bone, and its bottom wall is the nasopharyngeal apex, which is the site for NPC. The apical wall is the sella turcica of the skull base. The inner wall is the septum of sphenoidal sinus. The lateral wall is adjacent to the middle cranial fossa, cavernous sinus, internal carotid, and optic nerve. The ethmoid sinus is located in the ethmoid labyrinth between the lateral wall of the nasal cavity and the two orbits, being divided into the anterior, middle, and posterior groups based on position. The maxillary sinus is located in the maxillary body, and its posterior outer wall is adjacent to the pterypalatine fossa and the infratemporal fossa (Figure 2.3).

FIGURE 2.3. (A) Axial view of T1WI imaging: 1, ethmoid sinus; 2, sphenoid sinus. (B) Axial view of T1WI imaging: 1, maxillary sinus; 2, nasal septum; 3, nasal cavity; 4, choana. (C) Coronal view of T2WI imaging: 1, frontal sinus; 2, maxillary sinus; 3, middle nasal concha; 4, inferior nasal concha. (D) Coronal view of T2WI imaging: *, sphenoid sinus

A.4 Orbit

The orbit is a quadrangular pyramidal bone cavity containing the eyeball and accessory structures, which can be divided into the following four walls: (1) the upper wall of the orbit is composed of the orbital part of the frontal bone and the winglet of the sphenoid bone, adjacent to the anterior cranial fossa; (2) the inferior orbital wall is mainly composed of the maxilla, and below the inferior wall is the maxillary sinus; (3) the inner orbital wall is composed of the frontal process of maxilla, lacrimal bone, orbital plate of ethmoid bone, and sphenoid body, from front to back; and (4) the outer wall of the orbit consists of the zygomatic bone and the great wing of the sphenoid bone. The supraorbital fissure is located at the posterior part of the junction of the lateral orbital wall and the superior wall, and passes backward into the middle cranial fossa, through which the oculomotor nerve, trochlear nerve, abducent nerve, ophthalmic branch of trigeminal nerve, ophthalmic vein, and sympathetic nerve fibers pass. The infraorbital fissure is located at the posterior part of the junction of the lateral orbital wall and the inferior wall, and passes backward into the infratemporal fossa and pterygopalatine fossa, including the infraorbital nerve, the maxillary branch of the trigeminal nerve, the infraorbital artery, and the anastomotic branch of the infraorbital vein and the pterygopalatine venous plexus. The optic nerve foramen is located in the orbital apex and is vertically oval. It is formed by two branches of the sphenoid winglet, through which the optic nerve enters the middle cranial fossa and an ophthalmic artery enters the orbit from the skull (Figure 2.4).

FIGURE 2.4. (A) Axial position T2WI: 1, anterior chamber; 2, lens; 3, lacrimal gland; 4, vitreous; 5, optic nerve; 6, optic foramen; 7, medial rectus; 8, lateral rectus; 9, retrobulbar fat; 10, great wing of sphenoid bone. (B) Axial CT bone window: 1, supraorbital fissure; 2, anterior clinoid process; 3, great wing of sphenoid bone; 4, optic canal. (C) Axial CT bone window. The infraorbital fissure is shown by ↑. (D) Coronal CT bone window: 1, winglet of sphenoid bone; 2, supraorbital fissure; 3, infraorbital fissure; 4, optic canal; 5, great wing of sphenoid bone

A.5 Bone and foramens of the skull base

The staging and treatment plan of NPC are directly related to the skull base with or without bone destruction, which affects the disease prognosis. The bones that make up the skull base include the sphenoid bone in the middle, the occipital bone in the back, the temporal bone on both sides, the frontal bone in front, and the ethmoid bone. The skull base bone invasion of NPC is more common in the sphenoid bone, the base of the occipital bone, and the petrous part of the temporal bone.

The butterfly-shaped sphenoid bone resides in the center of the skull base, which is divided into four parts: the body, greater wing, lesser wing, and pterygoid process. The body is a cube-shaped bone mass in the central part containing the sphenoid sinus. The upper part of the body is the sella turcica and the central depression is called the pituitary fossa. The greater wing originates from both sides of the body and extends outward and upward. It is divided into the sunken cerebral surface, the anterior medial orbital surface, and the outer inferior temporal surface. The foramen rotundum, oval foramen, and spinous foramen lie at the root of the greater wing, from front to back. The maxillary branch of the trigeminal nerve passes through the foramen rotundum. The mandibular branch of the trigeminal nerve and the accessory meningeal artery pass through the oval foramen. The middle meningeal artery and the meningeal branch of the mandibular nerve pass through the spinous foramen. The lesser wing is a triangular sheet emanating from the front and top of the body. The upper part is the posterior part of the anterior cranial fossa and the lower part forms the posterior part of the superior orbital wall. There is an optic canal at the junction of the lesser wing and the body. The fissure between the lesser wing and the greater wing is the superior orbital fissure. The pterygoid process extends vertically downward from the greater wing body and the junction, and separates backward to form the medial plate and the lateral plate. The fossa between the two plates is called the pterygoid fossa. The pterygoid tubule root runs in a sagittal direction, called the pterygoid canal. The gap between the upper front of the pterygoid process and the back of the maxillary body is called the pterygomaxillary fissure, through which the terminal segment of the maxillary artery enters the pterygopalatine fossa. The sharp and downward pyramidal space surrounded by the pterygoid process, the maxillary body, and the palatine bone is called the pterygopalatine fossa. The anterior boundary is the maxilla, the posterior boundary is the pterygoid process, the top is under the sphenoid body, and the medial wall is the vertical part of the palatine bone. The pterygopalatine fossa is an important intersection point through the pterygoid maxillary fissure through the infratemporal fossa, the sphenopalatine foramen through the nasal cavity, the infraorbital fissure forward, the middle cranial fossa through the round foramen, and the pterygoid canal through the pterygoid canal, then moving down to the palatine canal and the palatine foramen. The contents of the pterygopalatine fossa include the internal maxillary artery, the maxillary nerve, and the sphenopalatine ganglion (Figure 2.5).

FIGURE 2.5. (A) Axial position T1WI: 1, maxillary sinus; 2, pterygopalatine fossa; 3, pterygoid maxillary fissure; 4, lateral plate of pterygoid process; 5, medial plate of pterygoid process. (B) Coronal T2WI: 1, sphenoid sinus; 2, foramen rotundum; 3, pterygoid process; 4, lateral plate of pterygoid process; 5, medial plate of pterygoid process; 6, lateral pterygoid muscle; 7, medial pterygoid muscle. (C) Axial CT bone window: 1, pterygopalatine fossa; 2, pterygoid maxillary fissure; 3, pterygoid canal. (D) Axial CT bone window: 1, maxillary sinus; 2, pterygopalatine fossa; 3, pterygoid maxillary fissure; 4, pterygoid process; 5, lateral plate of pterygoid process; 6, pterygoid fossa; 7, medial plate of pterygoid process. (E) Coronal CT bone window: 1, sphenoid sinus; 2, round hole; 3, pterygoid canal; 4, pterygoid process; 5, lateral plate of pterygoid process; 6, medial plate of pterygoid process. (F) Axial CT bone window: 1, foramen rotundum; 2, foramen ovale; 3, spinous foramen

The occipital bone is located in the posterior and lower part of the skull, which is spoon-shaped. There is a foramen magnum in the anterior and lower part of the occipital bone. The foramen magnum is divided into the following four parts: the basilar part in front, the squamous part at the back, and lateral parts at both sides. The lower part of the lateral part has an oval articular surface, called the occipital condyle. Outside of the occipital condyle, there is an irregular foramen at the junction of the occipital bone and the petrosal part of the temporal bone, called the jugular foramen. The jugular vein, glossopharyngeal nerve, vagus nerve, and accessory nerve pass through the jugular foramen. The hypoglossal canal is located in the anterolateral side of the occipital foramen, the posterior inferior medial side of the jugular foramen on both sides, and the upper part of the occipital condyle. It is a pair of bony channels from the posterior cranial fossa to the nasopharynx and carotid artery area, and the hypoglossal nerve runs in the canal.

The temporal bone is involved in forming the skull base and the lateral side of the cranial cavity. With the external auricular hilus as the center, the temporal bone is divided into squamous, tympanic, and petrosal parts. The fissure between the petrous part and the occipital bone is called the petrooccipital fissure. The subtriangular osseous hole surrounded by the sphenoid body, the base of the occipital bone, and the petrous apex is called the foramen lacerum, through which the internal carotid artery, deep petrosal nerve, and emissary vein pass. The foramen lacerum connects with the carotid sulcus on both sides of the sella turcica and posteriorly outward with the internal opening of the carotid canal in the petrous part of the temporal bone. The foramen lacerum is one of the main ways for NPC to invade the brain (Figure 2.6).

FIGURE 2.6. (A) Axial CT bone window: ↑ shows the hypoglossal canal. (B) Axial CT bone window: 1, foramen lacerum; 2, petrooccipital fissure; 3, carotid canal; 4, jugular foramen. (C) Axial CT bone window: * shows the carotid canal. (D) Axial T2WI: ↑ shows the hypoglossal canal. (E) Axial T2WI: 1, foramen lacerum; 2, petrooccipital fissure; 3, carotid canal; 4, jugular foramen. (F) * shows the carotid canal

A.6 Intracranial nerve

NPC can directly destroy the bone of the skull base or invade the brain through the fissure of the skull base foramen or the lymphatic ring of the skull base. The common sites of invasion include the cavernous sinus, the temporal region, and the cerebellopontine angle.

The cavernous sinus, located on both sides of the sella turcica, is an irregular space between the medial dura mater and the lateral endosteal layer. In the inner layer of the lateral wall of the cavernous sinus between the anterior clinoid process and the posterior clinoid process, the oculomotor nerve, trochlear nerve, ophthalmic nerve, and maxillary nerve are arranged in turn from top to bottom. Behind the posterior clinoid process, there are only the trochlear nerve and ophthalmic nerve in the lateral wall. The internal carotid artery and the abducent nerve pass through the cavernous sinus. The cavernous sinus is inward adjacent to the sella turcica and pituitary, with the sphenoid body in the lower part, anterior to the anterior clinoid process and supraorbital fissure, posterior to the posterior clinoid process and the petrous apex of the temporal bone, the medial meninges of the temporal lobe on the lateral side, and the Meckel' s cavity on the lateral inferior part. The Meckel's cavity is formed by the dura mater and arachnoid surrounding the trigeminal ganglion (Figure 2.7).

FIGURE 2.7. (A) Coronal T1WI+C: ↑ shows the cavernous sinus. (B) Coronal T2WI: ↑ shows Meckel's cavity

A.7 Cranial nerve

NPC spreads along the cranial nerve sheath or around the nerve, which is a way for the tumor to spread to non-adjacent areas. Imaging physicians should be familiar with normal cranial nerve anatomy and imaging findings, and the early diagnosis of tumor cranial nerve infiltration. There are 12 pairs of cranial nerves, of which III, IV, V, VI, and XII are most commonly involved in NPC infiltration.

The olfactory nerve is formed by the accumulation of the central processes of olfactory cells in the mucosa of the superior turbinate and the upper nasal septum, and the ethmoidal foramen through the nasal parietal wall enters the anterior cranial fossa and connects to the olfactory bulb. The optic nerve is concentrated by the axons of ganglion cells in the posterior part of the retina to form the optic disc, and the optic nerve is formed after passing through the scleral ethmoid plate. The optic nerve enters the middle cranial fossa through the optic canal and migrates to the optic chiasma of the diencephalon. The oculomotor nerve arises from the interpeduncular fossa of the midbrain, runs close to the edge of the tentorial notch and the posterior clinoid process, and enters the upper part of the lateral wall of the cavernous sinus and the orbit through the superior orbital fissure. The trochlear nerve originates from the inferior colliculus of the midbrain, goes forward around the lateral foot of the brain, passes through the lateral wall of the cavernous sinus, and enters the orbit through the superior orbital fissure. The trigeminal nerve comes out of the brain from the junction of the base of the pons and the middle peduncle of the cerebellum, and enters the Meckel's cavity, and then divides into the ophthalmic, maxillary, and mandibular nerves. After passing through the cavernous sinus, the ophthalmic nerve enters the orbit from the superior orbital fissure. After passing through the cavernous sinus, the maxillary nerve arises from the round foramen, enters the pterygopalatine fossa, and then enters the orbit through the infraorbital fissure. The mandibular nerve goes out of the skull from the foramen ovale and enters the space of the masticatory muscle, which is divided into the anterior and posterior trunk on the deep surface of the lateral pterygoid muscle. The abducent nerve arises from both sides of the midline of the bulbopontine sulcus, goes forward to the tip of the petrous part of the temporal bone, enters the cavernous sinus, moves along the outer lower part of the internal carotid artery in the sinus, and enters the orbit through the superior orbital fissure. The facial nerve comes out of the brain from the lateral part of the bulbopontine sulcus, reaches the fundus of internal auditory meatus through the internal acoustic porus and the internal auditory meatus, passes through the floor of the internal auditory canal into the facial nerve canal, and finally comes out of the skull from the stylomastoid foramen and passes forward through the parotid gland to the face. The vestibulocochlear nerve is connected to the lateral part of the bulbopontine sulcus and resides on the lateral side of the facial nerve. The glossopharyngeal nerve, vagus nerve, and accessory nerve come out of the brain from the posterior olive of the medulla oblongata, and out of the skull through the jugular foramen. The hypoglossal nerve arises from the brain between the medulla oblongata pyramid and the olive, and out of the skull through the hypoglossal canal (Figure 2.8).

FIGURE 2.8. (A) Coronal T1WI+C: 1, oculomotor nerve; 2, trochlear nerve; 3, ophthalmic nerve; 4, ophthalmic nerve; 5, ophthalmic nerve; 6, mandibular nerve, (B) Coronal T2WI: 1, ophthalmic nerve; 2, pterygoid nerve, (C) Axial T1WI: ↑ shows the hypoglossal nerve. (D) Axial T2WI: ↑ shows the facial nerve

Section 3: MRI features of NPC invasion to adjacent structures A.1 T stage of the 8th edition of the UICC/AJCC staging system for NPC

    

T category	T criteria
TX	Primary tumor cannot be assessed.
T0	No tumor identified, but EBV-positive cervical node(s) involvement.
T1	Tumor confined to nasopharynx, or extension to oropharynx and/or nasal cavity without parapharyngeal involvement.
T2	Tumor with extension to parapharyngeal space, and/or adjacent soft tissue involvement (medial pterygoid, lateral pterygoid, and anterior vertebral muscles).
T3	Tumor with infiltration of bony structures at skull base, cervical vertebra, pterygoid structures, and/or paranasal sinuses.
T4	Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle.

A.2 MRI features of NPC invasion to adjacent structures

NPC has the biological characteristics of infiltrative growth and easily invades the adjacent structures. It often breaks through the fascia of the base of the nasopharynx to both sides and invades the parapharyngeal space, masticatory muscle space, and parotid space, or spreads backward and upward to invade the paranasal sinus, skull base bone and intracranial, less forward invasion of the nasal cavity, and downward invasion of the oropharynx. According to the 8th edition of AJCC/UICC staging system, the NPC invasion of the surrounding structures belongs to the category of T staging. The accurate T staging is the basis not only for making accurate individualized treatment protocols, but also for guiding academic exchanges and carrying out multicenter clinical research.

The AJCC/UICC staging system (8th edition) staging for NPC has taken MRI as the preferred imaging method. Compared with CT, MRI has the following advantages in judging the invasion of adjacent structures: (1) MRI can clearly display the pharynx and skull base fascia, and accurately determine whether the primary lesion invades the parapharyngeal space and the extent; (2) MRI has higher resolution on nasopharyngeal mucosa, muscle, and fat space around the nasopharynx, can detect the nasopharyngeal minimal lesions early, and can accurately judge whether the tumor is hyper-cavity invaded; (3) MRI has higher sensitivity and detection rate for early bone marrow signal changes in NPC with skull base bone invasion; (4) MRI can effectively distinguish the benign lesions of nasal cavity and paranasal sinuses (inflammation, mucosal thickening or effusion) from tumor invasion; and (5) MRI can more clearly show that NPC spreads along the surface of nerves and blood vessels in the natural foramen or fissure of the skull base or directly destroy the skull base structure into the brain, especially the intracranial invasion of cavernous sinus, cerebellopontine angle, dura mater, and brain parenchyma. The detection rate based on MRI is significantly higher than that of CT.

MRI is also superior to CT in showing the retropharyngeal lymph nodes. MRI can effectively distinguish the lesions in the carotid sheath area from the direct invasion of primary tumor or enlarged retropharyngeal lymph nodes. In summary, MRI has higher detection rate and diagnostic accuracy in judging the NPC invasion of surrounding structures, which can effectively improve the accuracy of T staging.

A.2.1 Stage T1: Tumor confined to the nasopharynx or extension to oropharynx and/or nasal cavity without parapharyngeal involvement

NPC usually originates from the pharyngeal recess of the posterior nasopharyngeal wall, but can also originate from the posterior wall of the median parietal. It is easy to infiltrate the submucosa and spread along the muscle fiber bundles, neurovascular bundles, and fibrous adipose tissue spaces. The pharynx-skull base fascia is an important anatomical structure for the clinical division of T1 and T2 stages. The MRI findings depend on whether the fat space between the levator palatine muscle and the tensor palatine muscle is clear and continuous, and whether the high-signal fat space is filled by the medium-signal tumor tissue. MRI examination can clearly show the invasion of pharynx and skull base fascia in early lesions, and distinguish T1 and T2 lesions. The signal of the pharynx and skull base fascia is continuous, with linear low signals on T1WI and T2WI (Figures 3.1 and 3.2). The diagnosis of intraluminal lesions by CT mainly depends on the deformation of the pre-styloid fat space. The line between the medial pterygoid plate and the lateral margin of the internal carotid artery is the sign for pharynx and skull base fascia. CT diagnosis can also be considered as the invasion of parapharyngeal space if accompanied by the deformation of the peripharyngeal fat space. Therefore, CT diagnosis mainly depends on the indirect signs caused by the space-occupying effects of local lesions. However, the small size of the focus may also invade the fascia, while the large size of the focus may not invade the fascia, only push and shift it. The diagnosis of MRI mainly depends on direct signs of signal changes in the parapharyngeal fat space. MRI could help to distinguish between the direct invasion of the primary focus in the retrostyloid space and retropharyngeal lymph node enlargement. Only the pharynx skull base fascia is involved, but the parapharyngeal space is still in stage T1. The breakthrough of the pharynx skull base fascia involving the parapharyngeal space is in stage T2.

FIGURE 3.1. (A) Ax T2 IDeal and (B) Sag T1WI both showing that the tumor was confined to the nasopharyngeal cavity. The pharyngeal skull base fascia is a T2WI low signal band (arrow) from the posterior edge of the medial pterygoid plate to the anterior and outer edge of the internal carotid artery

FIGURE 3.2. (A) Ax T2 IDeal and (B) Ax T1WI both showing that the tumor involved the right nasal cavity forward, T2WI showed a slightly high signal and T1WI showed a low signal

Due to the direct communication between the nasal cavity and the nasopharynx and the lack of anatomical barrier, the tumor often invades the nasal cavity directly through the posterior nasal foramen. A rare route of nasal invasion is by the tumor invading the pterygopalatine fossa or pterygomaxillary fissure first, and then invading the nasal cavity through the sphenopalatine foramen. T1 tumors involving the nasal cavity and oropharynx are rarely seen (Figure 3.3).

FIGURE 3.3. (A) Sag T1WI and (B) Sag T1WI fs+C both showing that the tumor descends over the free edge of the velum palatinum and involves the oropharynx. The T1WI shows a low signal and the enhancement is obvious

A.2.2 T2 stage: Tumor invades the parapharyngeal space and/or adjacent soft tissues (medial and lateral pterygoid muscles, anterior vertebral muscle)

High signal of the parapharyngeal fat disappears or is compressed on T1WI when the tumor invades the parapharyngeal space and is replaced by the low signal of the tumor. The invasion and destruction of the pharyngeal skull base fascia can be clearly displayed on T2WI, and tumor tissue in the parapharyngeal space can be seen on T2WI+C. The tumor invades the pharyngeal skull base fascia and involves the parapharyngeal space, the tensor palatine muscle is thickened, and the margin is unclear. When the tumor invades the superficial space, the parapharyngeal fat space is displaced, deformed, and narrowed, and the fat line in the parapharyngeal space disappears. When the tumor invades the deep space, the tumor grows outwards and invades the carotid sheath. The fat space of the carotid sheath is occupied by soft tissue masses, the carotid sheath is compressed, displaced, and narrowed, and the styloid process is displaced (Figure 3.4).

FIGURE 3.4. (A) Ax T2 IDeal and (B) Ax T1 Ideal+C both showing that the tumor broke through the left pharyngeal skull base fascia and involved the left parapharyngeal space, and the signal was enhanced after the addition of contrast agent

In Chen and Hu's study, the common route by which nasopharyngeal carcinoma invades the masticator space is spread of the primary lesion through the parapharyngeal space, generally along the medial pterygoid muscle, proceeding from the inside to the outside, followed by the pterygoid muscle space, the lateral pterygoid muscle, masseter muscle, or tumors spread through the medial pterygoid plate to the part where the medial pterygoid muscle attaches to the inner edge of the lateral pterygoid plate. After the tumor breaks through the fascia of the pharyngeal skull base, it can also directly invade the lateral pterygoid muscles along the lateral surface of the skull base. Nasopharyngeal tumors that invade the temporalis and masseter muscles are relatively rare. When the tumor involves the lateral pterygoid muscle, attention should be paid to the structure above the zygomatic arch such as the temporalis muscle in the masticator space. Nasopharyngeal carcinoma can also damage the root of the processus pterygoideus, the medial and lateral pterygoid plate, the medial and lateral pterygoid muscles, and the pterygopalatine fossa and the pterygomandibular space. It can invade the lateral pterygoid muscle alone. The larger the tumor is, the wider the area of the masticator space invaded. When the tumor invades the medial and lateral pterygoid muscles simultaneously, the blood vessels and nerves around the pterygoid space and the lateral pterygoid muscle will be entrapped by the tumor (Figures 3.5 and 3.6).

FIGURE 3.5. (A) Ax T2WI-STIR and (B) Cor T1WI fs+C both showing that the tumor involves the left parapharyngeal space and then spreads to the left medial pterygoid

FIGURE 3.6. (A) Ax T2WI-STIR and (B) Ax T1WI fs+C both showing that the tumor broke through the right pharyngeal skull base fascia and involved the right parapharyngeal space and then spread to the right medial and lateral pterygoid muscles

When nasopharyngeal carcinoma involves the prevertebral muscles, the subcutaneous fat compartments around the muscles disappear, resulting in unclear muscle boundaries. High signals of the invaded muscles are shown on T2WI, the normal muscle bundle structure disappears, and there is a markedly enhanced tumor signal within the moderately enhanced muscle signal in the enhanced scan (Figure 3.7). In the study of Liao et al., the incidence of prevertebral muscle invasion evaluated by MRI and CT was 36% and 18.4%, respectively.

FIGURE 3.7. (A) Ax T2WI-STIR and (B) Ax T1WI fs+C both showing that the tumor broke through the pharyngeal skull base fascia and involved the anterior vertebral muscles, and the signal was enhanced after the addition of contrast agent

A.2.3 T3 stage: Tumor invades the skull base, cervical vertebra, pterygoid structure, and/or paranasal sinus

NPC invades the intracranial mainly through the skull base or neural foramen. The nasopharynx is adjacent to the skull base, and the anatomic location is deep and hidden. Whether or not the NPC invades the skull base bone is related to the design of the radiotherapy plan. There are three types of MRI features for NPC skull base invasion:

(1) cortical bone involvement: low signal line disappears on T2WI and T1WI, which is replaced by a slightly low signal on T1WI and a slightly high abnormal signal on T2WI. The lesion area is significantly enhanced on T1WI with fat compression enhancement.

(2) cancellous bone involvement: the high signal on T1WI and slightly high signal on T2WI are changed, replaced by a slightly low signal on T1WI and a slightly high signal on T2WI. The lesion area is obviously enhanced on T1WI with fat-pressing enhancement.

(3) cranial nerves and vascular foramen: slightly low signal on T1WI, slightly high signal on T2WI, and obvious enhancement on T1WI. MRI is the best way to show the bone marrow of the skull base.

MRI can detect lesions in the early stage when the local trabecular bone has not been destroyed but the tumor has infiltrated into the bone marrow cavity. MRI is more sensitive than CT in showing the spread of NPC along the cranial nerve and the early changes in the bone marrow of the skull base. The neural foramen and ruptured foramen on the skull base bone are the main ways for the tumor to enter the brain. When the tumor enters the brain through the foramen, it is not necessarily accompanied by widening of the foramen and destruction of the surrounding bone, which are difficult to observe by CT. MRI shows that the normal signal in the craniocerebral foramen related to the tumor growth pathway disappears, and the soft tissue shadow is full of abnormal signal. The enhancement has the same intensity as the nasopharyngeal tumor. The rupture foramen is located at the top of the pharyngeal crypt, which is a triangle with the tip upward. It is a common way for nasopharyngeal tumors to invade the cavernous sinus. The bone invasion rate of the skull base is higher than that of the skull base foramen. The skull base bone is extensive. The bone adjacent to the nasopharynx includes the pterygoid process, clivus, and sphenoid sinus floor, which are easily invaded by the tumor. CT is superior to MRI in showing the cortex of the skull base. NPC lesions rarely invade the cervicalvertebra, especially for T3 stage NPC.

The main MRI features of NPC with sinus invasion include bone destruction and continuity interruption of the sinus wall, inhomogeneous thickening of sinus wall mucosa, accompanied by sinus cavity effusion, a mass in the sinus cavity connected with the nasopharyngeal tumor, forming a whole body, with the same degree of enhancement after enhancement, and soft tissue showing equal or slightly low signal on T1WI and equal or slightly high signal on T2WI. The enhanced MRI scan shows significant enhancement. Research has shown that the incidence of nasal sinus involvement in NPC is 14.2%, including 13.1% in sphenoid sinus, 3.2% in ethmoid sinus, and 2.1% in maxillary sinus. The tumor invades the sphenoid sinus mainly by destroying the base of the sphenoid sinus upward, and then invades the anterior wall of the sphenoid sinus backward through the ethmoid sinus. The tumor invades the ethmoid sinus mainly from the nasal cavity, and then from the sphenoid sinus. The main way of tumor invading maxillary sinus is to invade pterygoid process forward and then maxillary sinus forward, or to invade nasal cavity forward and then maxillary sinus outward. The coronal STIR and CE-T1WI show the sphenoid sinus invasion well, and the transverse T2WI sequence shows the ethmoid sinus and maxillary sinus invasion well. Therefore, MRI can detect more sinus invasion than CT, and provide more accurate and comprehensive imaging information, which is beneficial to the accurate delineation of the radiotherapy target (Figures 3.8 to 3.11).

FIGURE 3.8. NPC involving clivus. (A) Ax T2WI-STIR showing slightly high signal intensity. (B) T1WI showing low signal intensity. (C, D) Ax T1WI fs+C and SagT1WI fs+C showing obvious enhancement

FIGURE 3.9. (A) Plain CT scan showing the tumor destroying the greater wing of the sphenoid, clivus, and petrous apex of the right sphenoid bone. The right rupture hole is enlarged with soft tissue shadow inside. (B) Enhancement after intensification

FIGURE 3.10. (A) Ax T2 IDeal and (B) Cor T1 IDeal+C both showing that the nasopharyngeal tumor destroys the sphenoid sinus floor and involves the sphenoid sinus cavity. The signal intensity is slightly high on T2WI, and the tumor is significantly enhanced after enhancement, while the signal intensity of inflammation in the sphenoid sinus cavity is significantly high on T2WI

FIGURE 3.11. (A) Cor T2WI-STIR and (B) Ax T1WI FS+C all showing the tumor involving the anterior intervertebral space backward and then the C1 lateral mass

A.2.4 T4 stage: Tumor invades the brain, cranial nerve, hypopharynx, orbit, parotid gland, and/or extensive soft tissue invasion beyond the outer edge of the lateral pterygoid muscle

According to the 8th edition of AJCC/UICC staging system, the definition of masticatory muscle space invasion in NPC staging is pterygoid medial and lateral pterygoid muscle invasion alone as the T2 stage, while the T4 stage is defined as the tumor invading extensive soft tissues (such as the temporalis muscle and masseter muscle) beyond the lateral margin of the lateral pterygoid muscle. When the tumor invades to areas beyond the lateral edge of lateral pterygoid muscle, it can further spread outwards, involving the surrounding structures, such as the temporalis muscle and masseter muscle. The survival rate of NPC patients with medial and lateral pterygoid muscle invasion alone was significantly higher than that of patients with extensive soft tissue invasion beyond the lateral pterygoid muscle. The prognosis of NPC patients with tumor invasion beyond the lateral pterygoid muscle is poor, similar to that of patients with intracranial and cranial nerve invasion. However, tumor invasion of temporalis muscle and masseter muscle is rarely seen, mainly because both the temporalis muscle and masseter muscle are located on the lateral side of medial and lateral pterygoid muscle. The incidence of tumor invading the temporalis muscle and masseter muscle without other T4 structures is very low. One of the main ways for NPC to invade the temporalis and masseter muscles is through the parapharyngeal space, medial pterygoid muscle, and lateral pterygoid muscle. Therefore, when the temporalis and masseter muscles are involved in NPC, the medial and lateral pterygoid muscles are involved in most cases. In a few cases, NPC can also directly invade the temporalis and masseter muscles through the pterygopalatine fossa or posterior maxillary sinus fat space. Clinically, cervical metastatic lymph nodes could break through the capsule and directly invade the temporalis and masseter muscles. The parotid space is located outside the masticatory muscle space, parapharyngeal space, and carotid sheath space. Because the deep lobe of the parotid gland is adjacent to the carotid sheath space and parapharyngeal space, most tumors can directly invade the deep lobe of the parotid gland through the parapharyngeal space and carotid sheath space. Moreover, some tumors can also invade the parotid gland through the masticatory muscle space. The main MRI features of NPC with parotid gland invasion include the unclear boundary between tumor tissue and parotid gland, and the capsule of the parotid gland adjacent to tumor could be thickened and enhanced. In some cases, part of parotid gland tissue would be replaced by tumor signal and connected with the primary tumor, showing a slightly high signal on T2WI, with obvious enhancement on the enhanced scan, and the enhancement degree is the same as for the primary tumor.

The T4 stage is also defined as the NPC invading more than oropharynx and involving the hypopharyngeal structure. Anatomically, the boundary between the oropharynx and hypopharynx is the valley of epiglottis (equivalent to the lower edge of the C3 vertebral body). These two anatomical structures can be easily located and clearly shown on CT or MRI. Therefore, when the nasopharyngeal tumor invades downward along the pharyngeal mucosa beyond the level of the epiglottic valley or the lower edge of C3, it can be considered as hypopharyngeal invasion, which can be clearly displayed and judged on the sagittal and coronal MRI images, indicating that the tumor invades down the epiglottic valley. Clinically, it is rare for NPC lesions to invade the hypopharynx, and the vast majority of cases are accompanied by other T4 structures.

Because of the high location of the orbit, orbital invasion of NPC is relatively rare, with a reported incidence rate of about 3%. The clinical manifestations of most patients include exophthalmos, diminution of vision, diplopia, eye pain, blepharoptosis, and strabismus. MRI can clearly show the route of orbital invasion through the multidimensional plane: up through the lacerated foramen, cavernous sinus invasion of the supraorbital fissure or orbital apex, forward through the pterygopalatine fossa invasion of the infraorbital fissure or orbital apex, or forward through the ethmoid sinus direct invasion of the medial orbital wall. MRI often shows that the normal fat hyperintensity disappears on T1WI, with hyperintensity on T2WI. Local abnormal soft tissue tumor signal formation may also be seen. Uneven and obvious enhancement could be observed after enhanced scan. Corresponding bone destruction of the sinus or orbital walls and the invasion of the optic nerve or rectus oculi could also show significant thickening of the structure with abnormal signal and obvious enhancement. Because the superior orbital fissure is the passage for the III,IV,V1, and VI, cranial nerves, the optic foramen of the infraorbital fissure and the orbital apex are the passages for theV2 and II cranial nerves, respectively. When the orbit is invaded, the incidence of cranial nerve invasion will be greatly increased, and most patients with orbital invasion are accompanied by extensive peripheral structure invasion, often with poor prognosis.

The main routes and MRI features for NPC invading the brain are as follows:

(1) Breaking through the base wall of sphenoid sinus and then invading the sphenoid sinus and cavernous sinus. The main findings indicate that the soft tissue mass in the sphenoid sinus is connected to the primary focus of the nasopharynx, and the lesion invades the cavernous sinus, inferior temporal meninges, and/or brain parenchyma on one or both sides.

(2) The cerebellopontine area and the posterior cerebellopontine meninges are involved in the destruction of the occipital clivus or the posterior cerebellopontine meninges are invaded through the internal jugular foramen and hypoglossal canal of the occipital bone, usually showing irregular thickening of the meninges and obvious abnormal enhancement could be observed after enhanced scan.

(3) The cavernous sinus and temporal lobe are invaded along the internal carotid artery through the foramen lacerum.

(4) Breaking through the foramen lacerum upward, the greater wing of the sphenoid forward is involved, which then enters the intracranial, followed by invasion of the cavernous sinus, meninges, and brain parenchyma.

(5) Some lesions can invade the ethmoid sinus and frontal lobe parenchyma through the base of anterior cranial fossa.

Axial and coronal enhanced MRI images can clearly show that the primary nasopharyngeal tumor passes through the skull base foramen and connects with the intracranial lesions, with dumbbell-like changes in some images. When the tumor invades the occipital clivus in a wide area, the dorsum sellae and pituitary fossa are further involved. The normal anatomical morphology of the dorsum sellae is blurred or disappears, and the tumor tissue is partially embedded or directly immersed in the pituitary tissue.

The cavernous sinus and Meckel's cavity are located at the bottom of the middle cranial fossa, on both sides of the sella turcica and pituitary gland, above the foramen lacerum, forming a long and narrow irregular hexahedral structure. The structure is a venous plexus of varying thickness around the internal carotid artery, surrounded by the dura mater. The III, IV, V1, and V2 cranial nerves run from top to bottom in the lateral wall of the cavernous sinus, while the internal carotid artery and sixth cranial nerve run in it, containing the fibrous trabeculae (sponge-like). The Meckel's cavity is the dural recess of the lateral wall of the cavernous sinus, containing the cerebrospinal fluid and trigeminal ganglion. The trigeminal ganglion and its branches in the Meckel's cavity and cavernous sinus can be easily seen on high-quality MRI images. Anatomically, the maxillary branch and the ophthalmic branch of the trigeminal nerve are located under and outside the abducens nerve. When the tumor invades the cavernous sinus through the foramen ovale and foramen lacerum, the maxillary branch and the ophthalmic branch of the trigeminal nerve are invaded first, while the abducens nerve is deep and usually invaded later.

The III, IV, V, VI, and XII cranial nerves are the most common types of infiltration in NPC, mainly tumor or various pathological factors infiltrating along the endoneuriu, perineurium or perineural. Perineural invasion of NPC often indicates poor prognosis. The survival rate and local control rate of these patients are significantly reduced. In clinical work, the diagnostic criteria of pericranial nerve infiltration are mainly based on the patient's symptoms and physical examination (whether there is cranial nerve paralysis). However, the location of peripheral cranial nerve infiltration in NPC is usually deep. The clinical symptoms and signs are often late, or even no symptoms are seen, thus it is difficult to find or detect by clinical physical examination, therefore MRI plays an important role in the early diagnosis and determination of peripheral cranial nerve infiltration in NPC. Reports have shown that the MRI diagnosis of NPC cranial nerve infiltration is significantly better than that of the clinical physical examination. One of the reasons can be analyzed from the aspect of pathophysiological mechanism, in which the tumor cells spread along the perineurium and sheath, and do not damage the nerve fibers or their continuity. Cranial nerve function can still be compensated, and no cranial nerve paralysis would be induced at this time. However, as the tumor cells continue to grow to the nerve fibers, the nerve fibers are be destroyed and interrupted. However, the nerve function cannot be compensated and thus symptoms of cranial nerve paralysis appear. Other reasons may be the low sensitivity of some patients to cranial nerve symptoms or careless clinical physical examination. Studies have shown that in T3 and T4 patients, the 3-year overall survival rate and distant metastasis-free survival rate of a cranial nerve invasion group diagnosed by MRI are significantly lower than those of non cranial nerve invasion group. There were no significant differences in the 3-year overall survival rate, distant metastasis-free survival rate, and local recurrence free survival rate between a cranial nerve palsy group and a cranial nerve palsy group diagnosed by MRI. Therefore, it is reasonable to take MRI and clinical examination of cranial nerve palsy as the diagnostic criteria of cranial nerve infiltration.

MRI features of perineural invasion in NPC are (1) the cranial nerve or ganglion is abnormally thickened or enlarged, and the strengthened cranial nerve sheath (surrounding) shows irregular enhancement or forms soft tissue nodules or masses, (2) the cavernous sinus is abnormally widened, and the signal and enhancement of some soft tissues are the same as in the primary tumor, (3) Meckel's cavity becomes smaller or disappears, and the irregular soft tissue nodules or masses can be seen adjacent to the semilunar ganglion, and (4) the cranial nerve foramen is enlarged and widened asymmetrically. The bone structure of the foramen wall is destroyed, and the normal structure is replaced by tumor. MRI can clearly show the invasion of the cranial nerve foramen and the internal cranial nerve by the tumor, while an enhanced scan can show this more clearly. Expansion, widening or adjacent bone destruction of the cranial foramen, and clinical symptoms of cranial nerve palsy, can help to make the final diagnosis of cranial nerve invasion.

MRI can also clearly show the path of perineural invasion, including the following channels:

(1) Thefirst pair of cranial nerves from the ethmoid plate to the olfactory area of the upper third of the nasal cavity, which is rarely invaded by the NPC primary tumor.

(2) When the tumor invades the orbit, it often infiltrates the second to sixth cranial nerves through invading the inferior orbital fissure, superior orbital fissure, and orbital apex.

(3) When the tumor invades the pterygopalatine fossa, the tumor may further invade the foramen rotundum inferior orbital fissure or maxillary nerve (V2).

(4) When the tumor invades the parapharyngeal space through the pharyngobasilar fascia, it often infiltrates the mandibular nerve (V3) and then invades the cavernous sinus or Meckel's cavity via the foramen ovale. However, if the tumor invades the rupture hole or the greater wing of the sphenoid bone, it may further invade the mandibular nerve through the foramen ovale.

(5) The sixth cranial nerve starts from the abducens nucleus of pons to the petrous apex of temporal bone, and then penetrates into the cavernous sinus going along the external and inferior part of internal carotid artery, finally entering the orbit through the superior orbital fissure, which could easily be infiltrated by the primary tumor. The reason for the injury of abducens nerve is not due to its length, but its anatomical characteristics.

(6) The seventh and eighth cranial nerves are located in the petrous bone, so the incidence of cranial nerve injury is low, but the seventh cranial nerve passes through the parotid gland to the face via the stylomastoid foramen, and the incidence of the seventh cranial nerve invasion would be significantly increased when the primary tumor invades from the stylomastoid foramen to the deep lobe of the parotid gland.

(7) When the tumor invades the occipital bone and the post-styloid space, it often invades the sublingual nerve canal and the jugular foramen, involving the ninth to the twelfth cranial nerves. In addition, when the tumor invades the carotid sheath via the parapharyngeal space, the ninth to the eleventh cranial nerves may be involved.

NPC most frequently involves the trigeminal nerve and branches. In anatomy, the trigeminal nerve could be divided into the ophthalmic nerve, maxillary nerve, and mandibular nerve in Meckel's cave after it exits from the pons. After issuing from the trigeminal ganglion, the ophthalmic nerve passes through the lateral wall of the cavernous sinus, located below the accompanying oculomotor nerve and trochlear nerve, and then enters the orbit through the supraorbital fissure. After the maxillary nerve enters the lateral wall of the cavernous sinus, it leaves the cranial fossa along the lower part through the foramen rotundum and enters the pterygopalatine fossa, which then cracks into the orbit through the infraorbital fissure. The maxillary nerve is the lowest in the cavernous sinus, which is easier to be invaded. Therefore, once NPC invades the pterygopalatine fossa, the tumor is easy to invade the intracranial along retrograde foramen rotundum and cavernous sinus along the maxillary nerve. Since the suborbital fissure is the place where the maxillary nerve enters the orbit, it is also a common site for infiltration around the maxillary nerve. The mandibular nerve enters the masticatory muscle space after leaving the cranial fossa through the foramen ovale, which are divided into the anterior and posterior shafts on the deep surface of the lateral pterygoid muscle. When the NPC involves the space between the medialinner and lateral pterygium, the tumor is easy to retrograde along the mandibular nerve and invade the intracranial by destroying the foramen ovale. On the axial and coronal images, the mandibular nerve is irregularly incrassated, with obvious contrast enhancement, and the ipsilateral foramen ovale is damaged and enlarged. Meckel's cave, a space containing the trigeminal ganglion and trigeminal pool, is surrounded by the dura mater. The trigeminal ganglion and Meckel's cave are intermediate links of tumor infiltration of cerebral nerves. Meckel's cave shows significantly high signal intensity on T2WI MR imaging because it is filled with cerebrospinal fluid. NPC often infiltrates along the trigeminal nerve and invades the trigeminal ganglion retroactively, which is manifested as the disappearance of the local cerebrospinal fluid signal. Meckel's cave is smaller or disappears compared with the healthy side, and significant high signal intensity could be visible in the cave (Figures 3.12 to 3.20).

FIGURE 3.12. (A) Axial T2WI-STIR showing high signal of nasopharyngeal masses, invading the hypopharynx downward (white arrow). (B) Sagittal T1WI+C (FS) and (C) coronal T1WI+C (FS) both showing significant tumor enhancement of nasopharyngeal mass, descending beyond the epiglottic valley and lower margin of C3, and involving the laryngopharynx (white arrow)

FIGURE 3.13. (A) Axial T1WI+C (FS) and (B) coronal T1WI+C (FS) showing the primary lesions of NPC significantly enhanced with blurred boundaries. The right parapharyngeal space is broken. The medial pterygoid muscle and lateral pterygoid muscle are invaded, extended to the right temporalis muscle (white arrow)

FIGURE 3.14. (A) axial T2WI STIR, (B) axial T1WI+C (FS), and (C) coronary T1WI+C (FS) positions, the nasopharyngeal masses break laterally through the left parapharyngeal space and the carotid sheath space, further invading the deep lobe of the left parotid gland (white arrow)

FIGURE 3.15. (A) Axial T1WI-FSE showing that the tumor is outward with equal signals, blurring with the boundary of the left medial pterygoid muscle and lateral pterygoid muscle, reaching backward to the outer aperture of the left hypoglossal canal, with broadened left aperture. (B) Axial T2WI-STIR and (C) axial T1WI+C (FS) showing that the mass involves the left parapharyngeal space, the left medial pterygoid muscle and lateral pterygoid muscle, and the deep lobe of the left parotid gland (short white arrow). The left mandibular nerve is abnormally incrassated with slightly higher T2WI signal, which is significantly enhanced by an enhanced scan (short black arrow). The tumor also invades backward the left hypoglossal nerve. The left hypoglossal nerve is incrassated with slightly higher T2WI signal and significantly enhanced by an enhanced scan (long white arrow)

FIGURE 3.16. (A) Axial T2WI-STIR showing a slightly higher signal of a tumor invading the right foramen ovale upward, broadening of the right foramen ovale, and abnormal incrassation of the right mandibular nerve inside (white arrow). (B) Axial T1WI+C(FS) and (C) coronal T1WI+C(FS) both showing the enlargement and broadening of the right foramen ovale, irregular broadening, and significantly abnormal enhancement of the internal mandibular nerve (white arrow), while the shape, size, and signal of the left foramen ovale are generally normal

FIGURE 3.17. (A) Axial T2WI-STIR showing a slightly higher signal of a tumor invading the sphenoid body, the right wing of sphenoid, the right foramina of oval, the right cavern sinus, and Meckel's cave (long white arrow). (B) Axial T1WI+C (FS) showing obvious tumor enhancement, which invades the right cavernous sinus and Meckel's cave (long white arrow), and the posterior meninges of the slope upward through the right fora ovale (long white arrow). (C) Coronal T1WI+C (FS) more intuitively showing the upward invasion path of NPC to the intracranial, that is, the tumor invades the right cavernous sinus and Meckel's cave through the right foramina ovale (long white arrow)

FIGURE 3.18. (A) Axial T2WI-STIR and (b) Axial T1WI+C (FS) showing that the tumor invades the right orbital upward, and the involved right rectus muscle (long white arrow) and optic nerve (short white arrow) are significantly enlarged, showing slightly longer T2 signal, which is significantly enhanced by an enhanced scan

FIGURE 3.19. (A) Axial T1WI+C (FS) showing that the tumor invades the right nasal cavity, the right ethmoid sinus, the right pterygoid fossa, and the right foramen rotundum (long white arrow) in the front and upper part. The structure of the right foramen rotundum disappears and the local soft tissue mass with obvious enhancement can be seen. The lesion further invades the right cavernous sinus, Meckel's cave, and meninges backward and upward. (B) Coronal T2WI-STIR intuitively showing the path of nasopharyngeal masses invading the intracranial structures through the right foramen rotundum (long white arrow)

FIGURE 3.20. (A) Axial T1WI-FSE, (B) axial T2WI-STIR, and (C) axial T1WI+C(FS) showing that the nasopharyngeal tumor primary foci invades the left anterior vertebral muscle and base of the occipital bone of skull base backward, left hypoglossal canal, and left jugular foramen, which are invaded and destroyed by the tumor (white arrow), with unclear structure, presenting isointense t1 and mixed long T2 signal, enhanced significantly in the enhanced scan

Reference for delineation of target volumes in NPC

Target volumes for NPC irradiation include the gross nasopharyngeal tumor volume, metastatic cervical lymph nodes volume, subclinical lesions volume, and prevention volume. The delineation of the target volumes is based on MRI, and the detailed clinical examination of the anterior nasal space, nasopharynx, and oral cavity by endoscopy and CT and PET/CT images to fully evaluate the scope of tumor invasion and to avoid or reduce the irradiation of vital organs as much as possible. Delineation by enhanced MRI and planned CT may be alternative choices. The definition and delineation principles of target volumes are as follows:

• Gross tumor volume of NPC (GTVnx). The primary tumor area of the nasopharynx as observed by the clinical and imaging examinations, including the metastatic retropharyngeal lymph nodes.

• Gross tumor volume of cervix node (GTVnd). Enlarged lymph nodes observed by clinical examination and/or imaging. When delineating the target volume, multiple GTVnds can be set according to multiple cervical lymph nodes on both necks.

• Clinical target volume 1 (CTV1). GTVnx plus the surrounding subclinical lesion volume (i.e., GTVnx+5 mm = CTV1).

• Clinical target volume 2 (CTV2). CTV1 plus an additional 5 mm rim of tissue (i.e., CTV1+5 mm = CTV2). It is necessary to fully consider the nasopharyngeal anatomy and the biological characteristics of the tumor. According to the tumor invasion site and T stages, posterior nasal cavity, posterior maxillary sinus, pterygopalatine fossa, part of the posterior ethmoid sinus, parapharyngeal space, cranial bottom, part of the cervical spine, and clivus should be appropriately covered by CVT2. The specific anatomical boundaries and the scope are as follows:

• ① Anterior boundary: 5 mm behind the nasal cavity and 5 mm behind the maxillary sinus should be covered.
• ② Posterior boundary: If the clivus is not invaded, the front third of the clivus should be covered; if invaded, the entire clivus should be covered.
• ③ Superior boundary: The vomer and surrounding ethmoid sinus should be included. If the sphenoid sinus is invaded, the upper part of the posterior ethmoid sinus should be covered. Generally, the anterior ethmoid sinus needs no protection from irradiation. For lesions of T1 and T2 stages, the lower part of the sphenoid sinus should be covered, while for lesions of T3 and T4 stages, the entire sphenoid sinus should be covered. For lesions of T1 and T2 stages, the cavernous sinus does not need to be covered. For lesions of T3 and T4 stages, only the ipsilateral entire cavernous sinus should be covered. Regardless of the T stages, the bilateral foramen ovale, round foramen, and ruptured foramen should be covered. In a setting of posterior and lateral infiltration by the primary tumor or enlarged high cervical lymph nodes, the jugular foramen and hypoglossal nerve tube should be covered.
• ④ Lateral boundary: The entire parapharyngeal space should be covered regardless of T stage.

In addition, CTV2 should also cover GTVnd, the postpharyngeal lymph node volume, and the cervical lymph node drainage volume (CTVnd) that needs preventive irradiation, as follows:

Postpharyngeallymph node area. As the first site of nasopharyngeal lymphatic drainage, the posterior pharyngeal lymph node is adjacent to and closely related to the location of the primary tumor.^65,66 Therefore, the CTV of the postpharyngeal lymph node should be delineated according to the primary tumor CTV1 and CTV2. In addition, regardless of whether there is metastasis, the bilateral retropharyngeal lymph node area should be covered in CTV2. According to anatomical location and metastatic characteristics, the superior boundary is defined as the base of the skull, while the inferior boundary is defined as the lower edge of the C2 vertebral body, which can be extended to the lower edge of the C3 vertebral body if necessary. It should be pointed out that under normal circumstances, CTV2 only needs to cover the posterior pharyngeal lymph node area of the lateral group. Lin et al.⁶³ have proposed that the medial retropharyngeal lymph node should also be included in CTV2. However, rare metastasis is observed in this group.^65,67 Moreover, expanding the irradiation range will inevitably cause damage to adjacent muscles, thereby increasing the risk of complications such as dysphagia.^68,69 Thus, the feasibility of this delineation method remains to be verified.

• CTVnd. Preventive irradiation of the whole cervical lymph nodes in the I–V area is recommended for all NPC patients except N0 in RTOG.^70,71 With the development of modern radiography technology, the ability to diagnose NPC lymph node metastasis has greatly improved, and the pattern of lymphatic spread has also been revealed.⁷² More and more clinical evidence shows that elective neck irradiation (ENI) can reduce the incidence of complications without reducing efficacy,^73,74 therefore delineation by the ENI method should be recommended.

• N0 stage CTVnd. When there are no enlarged or suspected metastatic lymph nodes, only the bilateral areas II,III, and Va should be covered. When there are only unilateral cervical lymph nodes with suspicious metastases (high-risk areas, enlarged, but without reaching the positive standard), the ipsilateral II–V area and the contralateral II, III, and Va areas should be covered. If there are bilateral suspicious metastatic lymph nodes, the bilateral II–V area should be covered.

• N1-3 stage CTVnd. When there is only unilateral cervical lymph node metastasis, the ipsilateral II–V area and the contralateral II, III, and Va areas should be covered. If there are bilateral metastatic lymph nodes, the bilateral II–V area should be covered.

• CTVnd in Ib area. Because the lymph node metastasis and recurrence are rare in the Ib area,⁷⁵ covering the Ib area will increase the irradiated volume of submandibular glands and exacerbate dry mouth.⁷⁶ Therefore, it is generally not recommended to cover the Ib area within the target volume. If the following conditions occur, however, the ipsilateral Ib area can be considered to be included in CTVnd^62,77,78: metastatic lymph nodes in the Ib area or positive lymph node resection in the Ib area; extracapsular invasion or axial maximum diameter >2 cm of metastatic lymph nodes in zone II; metastatic lymph nodes in multiple areas (≥3) of the ipsilateral neck; tumor invasion in the submandibular gland; tumor invasion in the front half of the oral cavity or nasal cavity.

Notes: Unless the tumor invades the submandibular gland, the irradiated volume should be reduced as much as possible when delineating the CTVnd in the Ib area. Unless patients have received lymph node resection or the skin is invaded, the planned target area (PTVnd) corresponding to CTVnd should not exceed the edge of the skin, and it is recommended to be 2–3 mm below the skin.

If the tumor is adjacent to OAR, the delineation of the tumor is recommended to be expanded as follows: GTV+1 mm = CTVp1 and CTVp1+2 mm = CTVp2. Some experts suggest that for T3 and T4 primary tumors adjacent to OARs it is recommended that only CTV1 should be delineated and included the high risk area. There are various criterias for physians to balance target coverage with the protection of normal tissues.