Steve P. Lee, Maie A. St. John, Steven G. Wong, and Dennis A. Casciato
I. GENERAL ASPECTS OF HEAD AND NECK CANCERS. Head and neck cancers include a heterogeneous group of malignant tumors arising in all structures cephalad to the clavicles, except for the brain, spinal cord, base of the skull, and usually the skin. A meaningful understanding of these malignant tumors requires anatomic separation into those cancers arising in the oral cavity, oropharynx, hypopharynx, nasopharynx, larynx, nasal fossa, paranasal sinuses, thyroid and salivary glands, and vermilion surfaces.
A. Epidemiology and etiology
1. Incidence. The incidence of head and neck cancer continues to increase worldwide. Cancers arising in the head and neck constitute about 3% of all newly diagnosed cancers in humans. Head and neck cancer is the 10th most common cancer worldwide, with more than 45,000 new cases reported every year in the United States alone.
2. Etiology
a. Cigarette smoking and alcohol intake are the major risk factors. The use of tobacco products (including cigarettes, cigars, pipes, chewing tobacco, and snuff) and substantial alcohol intake are the major risk factors for head and neck carcinoma. Drinking alcohol and using tobacco at the same time more than doubles the risk of developing head and neck cancer.
Carcinogens in these products can induce molecular changes throughout the entire upper aerodigestive tract. Slaughter first described these changes, originating the concept of field carcinogenesis or “condemned mucosa” in 1953. Slaughter hypothesized that because of constant carcinogenic pressure, the entire upper aerodigestive tract is at increased risk of developing tumors. Head and neck cancer results from a multistep carcinogenesis process in which increasing degrees of mucosal changes and cellular atypia occur over large areas of the carcinogen-exposed upper aerodigestive tract epithelium. Of the survivors of one cancer of the head and neck, 20% develop another primary head and neck cancer.
b. Human papillomavirus (HPV) is now recognized as a risk factor for oropharyngeal cancer, independent of tobacco or alcohol usage. HPV-positive cancer cases are now in majority in the Western world, and these tumors are also shown to have better outcome than HPV-negative patients (discussed further in Section IV. Oropharynx. C.1).
B. Pathology
1. Histology. Nearly all cancers of the oral cavity and pharynx are squamous cell carcinomas of varying differentiation. Adenoid cystic and mucoepidermoid cancers arise from salivary glands. A range of histologically different cancers, such as papillary, follicular giant cell, Hürthle cell carcinomas, and lymphomas, arise in the thyroid gland.
2. Metastases. Most primary cancers of the head and neck spread by invasion of adjacent tissues and metastases to regional lymph nodes. Metastases to distant sites are infrequent. The most common location for distant metastases from head and neck cancers is the lungs.
C. Diagnosis
1. Common symptoms and signs
a. Painless mass
b. Local ulceration with or without pain
c. Referred pain to teeth or ear
d. Dysphagia, mechanical or painful
e. Alteration of speech, such as difficulty pronouncing words (tongue) or change in character (larynx, nasopharynx)
f. Persistent hoarseness (larynx)
g. Airway distress
h. Unilateral tonsillar enlargement in an adult
i. Persistent unilateral “sinusitis”
j. Persistent unilateral nosebleed or obstruction
k. Unilateral hearing loss often with serous otitis
l. Cranial nerve palsies
2. Biopsy and imaging. Primary cancers of the head and neck must be documented by biopsy. In some circumstances, epidermoid carcinoma is identified in a cervical lymph node and no obvious primary tumor can be found on physical or imaging examinations. This is described as cancers of unknown primary (CUP) or metastasis of unknown origin (MUO). “Blind” biopsies of Waldeyer ring are appropriate. Magnetic resonance imaging (MRI), computed tomography (CT), and PET/CT (positron emission tomography/CT) are used in establishing the local or regional extent of the tumor. Chest x-rays remain part of the evaluation, although intrathoracic metastases are infrequent.
3. Endoscopy. Visualization of the oral cavity, nasal cavity, nasopharynx, oropharynx, hypopharynx, larynx, cervical esophagus, and proximal trachea is essential in establishing the presence and extent of tumor. These examinations have been facilitated by development of flexible, small caliber, bright-light endoscopes. Biopsies should be done at the time of endoscopy. It is useful for all oncologists likely to be involved in the management of a specific patient to be present at the endoscopy.
4. Evaluation of masses in the neck. A new, firm, usually nontender mass or masses, in the neck, either unilateral or bilateral, especially in adults should be considered metastatic (or primary in the thyroid) cancer until proved otherwise. Before direct biopsy, search for a primary cancer is important. This search may include “blind” biopsies of Waldeyer ring and can include MRI, CT, and PET/CT examinations. Initial direct biopsy of a suspicious, enlarged cervical lymph can be done by fine-needle aspiration. Open biopsy should only be done as a last resort.
D. Staging. Staging can be based on clinical information or information found at surgery. Clinical staging is important because many patients are treated by radiation therapy (RT). Clinical staging is based on physical examination. All primary cancers must be documented histologically. If the biopsy was perfomed at another site, it is best if the pathology can be reviewed and documented at the treating institution.
The TNM system proposed by the American Joint Committee on Cancer (AJCC) is the most frequently used system in the United States (Table 7.1). T reflects primary tumor size and extension; N is based on the size, number, and location of cervical lymph node metastases; and M represents more distant metastases. The T staging classification varies slightly with the specific anatomic site and will be discussed with each cancer. The N and M classifications and stage groupings are the same for all head and neck cancers except nasopharyngeal carcinoma.
Table 7.1 TNM Staging for Head and Neck Cancers (Excluding Nasopharynx)a
aMelanoma and nonepithelial tumors (e.g., lymphomas, sarcomas) are excluded Adapted from the AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer-Verlag, 2010.
Stage IV is divided into three groups representing locally advanced but still resectable disease (IVA), unresectable locally advanced disease (IVB), and distant metastases (IVC).
E. Prognostic factors. The most important prognostic factors for patients with primary cancers of the head and neck are primary tumor site, size and extent, and regional or distant metastases. Histologic differentiation of epidermoid carcinomas is less important. A major risk factor is a previous head and neck cancer. Continued cigarette smoking and consumption of alcoholic beverages expose the mucosa to known carcinogens.
F. Prevention. The main preventatives for cancer of the head and neck are abstinence from the use of alcoholic beverages and tobacco. Also avoidance or elimination of chronic irritants, such as an irregular sharp tooth or ill-fitting denture, is desirable. Isoretinoin (13-cis-retinoic acid) can reverse severe leukoplakia and possibly reduce the development of squamous cell carcinomas in the oral cavity, but it has no influence on the recurrence of previously treated cancers. New saliva-based tests are being developed to screen those at high risk for developing head and neck cancer.
G. Management principles of head and neck cancers. Before commitment to a therapy program for a specific patient, there should be input from all members of the multidisciplinary oncology group who will be involved. Often patients with head and neck cancers present before a Tumor Board where they can benefit from the combined expertise of the multidisciplinary group. Included are surgeons, radiation oncologists, medical oncologists, dentists, nurses, psychologists, social workers, and rehabilitation personnel. Proper management includes frequent, periodic examinations after treatment. Persistent or “recurrent” cancers usually can be recognized within 2 years of the completion of treatment.
1. Surgery has long been a mainstay of the treatment of patients with cancers of the head and neck. Treatment of the primary tumor requires complete removal of the tumor and its local and regional extensions. Sometimes anatomic barriers, such as the base of the skull, make such complete removal unlikely. In such situations, adjuvant RT, chemotherapy, or both may facilitate or even negate the need for radical surgery. Recent advances have promoted adequate resection of some tumors involving the base of the skull.
a. Preservation of functions, such as swallowing, voice or vision, and cosmesis, must be considered in any management plan. Tumor extension into bone, such as the mandible or maxilla, usually requires resection. Often free flap reconstruction can minimize the long-term morbidity.
b. Metastases to cervical lymph nodes, particularly from the oral cavity, paranasal sinuses, hypopharynx, and thyroid, are best treated surgically, although postoperative irradiation frequently is indicated. Removal of cervical nodes containing metastatic cancer can be accomplished by en bloc resection (radical neck dissection) or a limited procedure, such as suprahyoid dissection or modified radical neck dissection.
2. RT can control many cancers of the head and neck, usually with better consequent function and cosmesis than following radical resection. No anatomic barriers to RT exist, although specific tissue tolerance limitations do. Basic radiobiologic principles must be observed in devising specific treatment approach (see Chapter 3).
a. Primary treatment. RT is used as the initial and possibly only therapy. This is done mainly to either preserve organs and functions or substitute for surgery for unresectable tumors.
b. Adjuvant treatment. RT is planned for use before or after surgery. The irradiated volume can be the preoperative or the postoperative tissue volume at risk, or it can be separate from the operative site, such as the treatment of cervical nodes after surgical removal of the primary tumor.
c. Volume treated. RT should include all known tumor-bearing anatomic sites plus any sites of suspected tumor spread, such as the neck in a patient with aggressive oral tongue or pharyngeal cancers.
d. RT doses. Included are incremental doses (usually in daily fractions) and total doses. Both relate to the probabilities of tumor control and treatment-related sequelae. In general, daily doses should be 180 to 200 cGy/fraction. For epidermoid carcinomas of the head and neck without surgery, the total doses are usually 6,500 to 7,500 cGy. When used as a postoperative adjuvant, the total doses can be lower (5,500 to 6,000 cGy), and when used preoperatively even lower doses (4,500 to 5,000 cGy) are appropriate.
e. Altered fractionation schemes. Special fractionation regimens have been created to exploit certain radiobiologic advantages for the treatment of head and neck cancers. (See Chapter 3, Section III.E.) They have been tested in numerous international phase-III multicenter randomized trials, and the results have in general been favorable as compared with conventional fractionation practice, especially for locoregionally advanced disease.
f. Hyperfractionation delivers more fractions with smaller dose per fraction to a higher total dose than conventional fractionation, over the same length of overall treatment time. It aims to enhance tumor cell killing while maintaining the same level of late normal tissue damage.
g. Accelerated fractionation aims to overcome the therapy-induced accelerated repopulation of cancer cells, and delivers a conventional amount of total dose while shortening the overall treatment time with more intensely fractionated patterns.
h. Combined chemoradiotherapy. In recent years, cytotoxic chemotherapy as well as biologic response modifiers have been shown to augment the therapeutic effect of RT. Most randomized trials have shown the benefit of concurrent chemo-RT (CCRT; see Section I.J.3.), while induction or neoadjuvant chemotherapy before definitive RT continues to be tested.
i. Precision-oriented RT. Recent advances in computer technology have enabled the development of ultraprecision treatment techniques, such as stereotactic irradiation and intensity modulated RT (IMRT). Particle therapy with protons and heavy ions are also available in a few centers worldwide (see Chapter 3, Sections IV.C., D.).
H. Management of the primary cancer
1. Most T1 and T2 primary cancers can be controlled equally well by surgery or RT. Therefore, the choice of treatment may be influenced by tumor site, accessibility, histologic grade, the patient’s health status, vocation, or preference. Organ or functional preservation may be provided by RT for cancers of the oral and pharyngeal tongue, floor of the mouth, larynx, orbit, or tonsil. Surgery is preferable when tumor involves bone.
2. Most T3 and T4 primary cancers often require combinations of surgery and RT. If resection is not possible, high-dose RT may still be effective and adjuvant chemotherapy may be useful. Although preoperative irradiation may reduce the tumor size and theoretically facilitate the surgery, postoperative irradiation is nearly always preferable because the extent of tumor can be better determined and tissue healing is less impaired. The total radiation doses after complete resection of the primary and regional tumors may be reduced to 5,500 to 6,000 cGy. Indications for postoperative RT include
a. Close or inadequate resection margins
b. Poorly differentiated cancers
c. Involvement of lymphatics, including cervical nodes
d. Perineural invasion
3. When cancer reappears clinically at the initial site following a complete response to the primary treatment, this is considered local recurrence of cancer. If a tumor arises at a different site, especially if the histology is different, it is considered a new cancer. The retreatment of cancers can be difficult, with reduced effectiveness and increased morbidity, although surgery may “rescue” failures of RT, and irradiation may control surgical failures.
a. Recurrence of a tumor usually indicates a biologically aggressive cancer and the prognosis is worse than before the initial treatment.
b. If the local failure is at the margin of the treatment site, it may be a direct result of “geographical miss,” and additional focal salvage treatment may still provide effective cure.
I. Treatment of metastases to cervical lymph nodes. The head and neck encompasses perhaps some of the most anatomically complicated regions of the body. Knowledge of the lymphatic system is essential in order to understand the pattern of spread of cancer in the neck. Most squamous cell carcinomas of the head and neck are at least potentially curable. Primary cancer arising in most sites in the head and neck ultimately metastasizes regionally to the cervical lymph nodes. As the status of these lymph nodes is the most significant independent prognostic factor in head and neck cancer, appropriate management of the cervical lymph nodes is essential for control of disease. Neck dissection is the standard surgical treatment for resecting cancer in the regional lymph nodes of the neck. The purpose of a neck dissection is to remove those lymph nodes involved by or at risk for involvement by metastatic cancer.
1. Types of neck dissection (ND). The Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology-Head and Neck Surgery reported classification of neck dissection terminology into four categories:
a. Classic radical ND removes en bloc all tissues from the clavicle to the mandible and from the anterior margin of the trapezius muscle to the midline strap muscles between the superficial layer of the deep cervical fascia (platysma) and the deep layer of the deep cervical fascia. Included are the sternocleidomastoid muscle, internal jugular vein, and accessory (11th) cranial nerve.
b. Modified radical ND usually spares the accessory (11th) nerve, the sternocleidomastoid muscle, or both. This operation is usually used when the neck is “clinically negative,” but at high risk for metastases or when the metastases to cervical nodes are minimal and when RT is to be used. A variant is the supraomohyoid dissection that removes nodes only from the upper neck.
c. Selective ND includes the possibility of dissection of supraomohyoid, posterolateral, lateral and anterior compartments, each representing a specific procedure that preserves one or more lymph node groups routinely removed in radical neck dissection.
d. Extended ND involves the removal of additional lymph node groups or nonlymphatic structures relative to the radical procedure.
2. The risk of clinically undetected metastases varies with primary tumor site and size and the histology. For example, approximately 40% of patients with squamous cell carcinomas of the oral tongue will eventually develop cervical adenopathy. This risk is higher, and often bilateral, for patients with carcinomas of the pharyngeal tongue. In contrast, cervical metastases do not develop in patients with cancers limited to the true vocal cords because there are no lymphatics.
3. Selection of treatment. When metastases to cervical lymph nodes are present at the time of diagnosis, treatment of the neck is usually dictated by the treatment modality selected for the primary tumor. For squamous cell carcinomas, primary in the oral cavity and paranasal sinuses, surgery may be preferable. When the cancers arise in the nasopharynx, RT is the choice because these tumors are radio-responsive; they often are bilateral and may not be resectable because of anatomic barriers. Other pharyngeal and laryngeal primary tumors would require both surgery and RT, but with cervical nodal metastases primary, RT with or without chemotherapy is preferable, often followed by planned ND.
4. Sentinel lymph node biopsy (SNB). In 1993, the first report was published describing the use of SNB for staging of head and neck squamous carcinoma. Even though subsequent successful studies have been performed, SNB for mucosal cancers of the upper aerodigestive tract should be evaluated only in the context of clinical trials. The place of SNB in staging and management of head and neck mucosal squamous cell carcinoma is still an ongoing debate and remains an investigational procedure. It has not achieved the status of “standard of care” for the treatment of head and neck cancer patients. It is recommended that studies of the efficacy of SNB strive, whenever possible, to segregate results of different tumor types in different head and neck locations from one another so as to produce more focused findings for discrete types of malignancies, and not group together tumor types which may in reality exhibit different biologic behaviors.
Recently, a rapid, automated quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) assay has been developed to detect lymph node metastasis in head and neck cancer with high accuracy compared to pathologic analysis and may be more accurate than intraoperative pathology. Combined, SNB and rapid qRT-PCR could more appropriately guide surgical treatment of patients with head and neck cancer.
5. Endoscopic neck dissection. Endoscopic selective neck dissection has been recently reported in patients suffering from squamous cell carcinoma of the upper aerodigestive tract located in different sites (uvula, epiglottis, and glottis). It is thought that this method may help to reduce the degree of invasiveness frequently attributed to sentinel lymphadenectomy once it has been established for head and neck cancer. At present this procedure has not achieved widespread acceptance in clinical practice.
6. Molecular approaches for the evaluation of lymph node metastases. Different methods have been used in preoperative biopsy specimens to predict neck metastases. Examples include the fraction of cancer cells immunolabeled for PCNA or Ki67, expression of E-cadherin, Snail and expression of MMP-2, MMP-7, and MMP-9, but these reports should be confirmed in larger multicenter trials.
Microarray expression profiles of more than 100 predictor genes on head and neck primary carcinomas, on the other hand, have been capable of discriminating between N+ and N0 individuals, with N0 predictive accuracy of 90%. It is highly possible that expression profiling will improve the diagnosis of nodal status, thus reducing adverse side effects related to overtreatment. The ability to predict cervical lymph node metastases based upon gene expression patterns present in a primary tumor biopsy sample would provide tremendous advantages for the determination of optimal therapeutic strategies. However, the correlations identified with the presence of nodal metastasis are inconsistent and not yet strong enough to be useful in clinical practice.
J. Role of chemotherapy in squamous cell carcinomas of the head and neck (SCCHN). Chemotherapy does not have a role in most early stage (I and II) SCCHN. The greatest benefit derived from chemotherapy is in patients with locally advanced disease when chemotherapy is used either sequentially or concurrently with RT, with or without surgery. It has been shown in this setting to increase the possibility of larynx preservation and improve survival. Data supporting adjuvant chemotherapy is largely restricted to nasopharyngeal carcinoma. In the metastatic setting, it may be used as a palliative measure and has also been shown to improve overall survival.
1. Effective agents. Many drugs have shown activity as single agents in the metastatic setting with potentially high response rates (RR) in phase II studies. Examples include methotrexate (RR 10% to 45%), cisplatin (RR 15% to 40%), bleomycin (RR 5% to 45%), 5-fluorouracil (5-FU; RR 0% to 33%), paclitaxel (RR 30% to 40%), docetaxel (RR 30% to 40%), carboplatin (RR 10% to 30%), ifosfamide (RR 25%), cetuximab (RR 16%), and erlotinib (RR 4%). These response rates often decrease significantly in phase III studies.
2. Induction chemotherapy (before surgery or RT) has been evaluated extensively. Despite very high RR, early studies did not show survival benefit with this approach. A meta-analysis has shown, however, a small but significant survival benefit when cisplatin and 5-FU are used in combination.
Several randomized studies in the United States and Europe have also shown a benefit when a taxane (usually docetaxel) is added to cisplatin/5-FU, given either before RT or CCRT. The Dana Farber group (TAX 324) showed a significant improvement in 3-year overall survival from 48% to 62% when docetaxel was added to cisplatin/5-FU, then followed by carboplatin given concurrently with RT. What is not known is whether the addition of any induction chemotherapy will improve survival compared with the optimal CCRT and studies are ongoing to address this question.
3. Induction chemotherapy regimens for SCCHN include
a. TPF, given in 21-day cycles
Docetaxel (Taxotere), 75 mg/m2, IV on day 1
Cisplatin, 75 mg/m2, IV on day 1
5-FU, 750 mg/m2/day by continuous IV infusion over 24 hours on days 1 through 5
b. TPF, also given in 21-day cycles
Docetaxel, 75 mg/m2, IV on day 1
Cisplatin, 100 mg/m2, IV on day 1
5-FU, 1,000 mg/m2/day by continuous IV infusion over 24 hours on days 1 through 4
4. Concurrent chemoradiotherapy (CCRT) has been shown to improve larynx preservation rates in intermediate, locally advanced laryngeal cancer by the Radiation Therapy Oncology Group (RTOG 91-11). A meta-analysis of CCRT used in patients with locally advanced SCCHN has shown a statistically significant improvement in overall survival (absolute improvement 8%). Survival benefits have been seen in randomized studies using various chemotherapy regimens, such as cisplatin alone, cisplatin with 5-FU, and carboplatin with 5-FU.
A study with cetuximab, a monoclonal antibody to the epidermal growth factor receptor, in combination with RT, has shown a significant survival benefit compared with RT alone (55% vs. 45% 3-year overall survival). Although CCRT using conventional cytotoxic agents will increase mucosal toxicity compared with RT alone, this increase in toxicity was not seen with cetuximab.
Although, a small (21 patients) single institution phase II study done at Memorial Sloan-Kettering Cancer Center evaluated the combination of cisplatin, cetuximab, and RT and showed an impressive 3-year overall survival rate of 76% in a group of highly selected patients with very advanced disease, this study was confounded by five significant adverse events, including two deaths. This finding was tested in a phase III cooperative group study (RTOG 05-22) of 895 patients, which showed that the addition of cetuximab did not improve either progression-free survival or overall survival (see Ang, 2011 in Selected Reading). Thus, single-agent cisplatin or cetuximab remains the standard of care for combination with RT for locally advanced HNSCC.
5. CCRT regimens for SCCHN include
a. Given in 21-day cycles for three cycles with RT:
Cisplatin, 100 mg/m2, IV on day 1
b. Given in 21-day cycles for 3 cycles with RT:
Carboplatin, 70 mg/m2, IV on days 1 through 4
5-FU, 600 mg/m2/day by continuous IV infusion over 24 hours on days 1 through 4
c. Cetuximab, 400 mg/m2 IV loading dose given on the week before RT starts, then 250 mg/m2 IV weekly for 7 weeks
d. Acceptable cisplatin alternative schedules for improved tolerability include 30 to 40 mg/m2 weekly, 6 mg/m2 daily, or 20 mg/m2 daily for 5 days on first and fifth weeks of RT.
e. If induction TPF is utilized, carboplatin AUC 1.5 given weekly with RT is acceptable.
6. Adjuvant chemotherapy is not recommended as standard of care after RT, with the single exception of nasopharyngeal carcinoma. In the Intergroup Study 0099, patients with stage III/IV nasopharyngeal carcinoma were randomized to RT alone or concurrent cisplatin and RT followed by three cycles of adjuvant cisplatin and 5-FU. The 3-year overall survival was 47% and 78%, respectively (P = 0.005), establishing this regimen with CCRT followed by adjuvant chemotherapy as the standard of care.
Although no benefit was seen with the use of RT alone (e.g., Intergroup 00-34) in the postoperative setting, several studies have evaluated CCRT in “high risk” patients. The two largest phase III randomized studies that have been completed were done by the European Organization for Research of Cancer (EORTC 22931) and the RTOG (RTOG 95-01). Both studies randomized patients to either high dose cisplatin as CCRT or RT alone and showed significant improvement in disease-free survival with cisplatin added. However, only EORTC 22931 showed a significant improvement in overall survival (absolute 13% survival benefit at 5 years). Subset analyses of both studies have shown that significant improvement in survival is seen only for patients with either extracapsular lymph node extension or positive surgical margins.
a. CCRT plus adjuvant regimen for nasopharyngeal carcinoma: Cisplatin, 100 mg/m2, IV on day 1 of 21-day cycles for three cycles concurrently with RT (alternatively, carboplatin AUC 6 may be substituted for cisplatin);
Followed by three 28-day cycles (after RT is completed) of Cisplatin, 80 mg/m2 IV on day 1 (or carboplatin AUC 5 if carboplatin used for combined portion), and
5-FU, 1,000 mg/m2/day by continuous IV infusion over 24 hours on days 1 through 4
b. Postoperative CCRT regimens for all other HNSCC (nonnasopharyngeal carcinomas):
(1) Cisplatin, 100 mg/m2, (or carboplatin AUC 6) IV on day 1 of 21-day cycles for three cycles concurrently with RT
(2) Standard weekly cetuximab 400 mg/m2 loading dose followed by 250 mg/m2
(3) Weekly carboplatin AUC 1.5 to 2
7. Reirradiation. The standard of care for patients with recurrent unresectable disease in a previously irradiated field is palliative chemotherapy. Several investigators, however, have evaluated the use of reirradiation concurrently with chemotherapy with overall 2- to 5-year survival rates ranging from 15% to 25%.
RTOG 99-11 evaluated hyperfractionated RT with cisplatin (15 mg/m2) and paclitaxel (20 mg/m2), both given daily for 5 days every 14 days for four cycles; treatment resulted in a 27% 2-year overall survival. However, this study resulted in an 8% grade 5 toxicity (death). Another unusual aspect is that growth factor was utilized concurrent with radiation on the days that chemotherapy was not being given. Given these uncertainties, despite the nice survival report, this approach is not recommended for routine use.
An early phase II study (RTOG 96-10) evaluated reirradiation using hyperfractionated RT with concurrent hydroxyurea (1.5 g) and 5-FU (300 mg/m2), both given daily for 5 days every 14 days for four cycles; treatment resulted in a 16% 2-year overall survival.
A phase III study to determine if this approach is superior to standard chemotherapy had to close early because of poor accrual. At this time, this highly toxic approach should be considered investigational and should not be done outside of a clinical trial or a center with extensive experience with this treatment.
8. Metastatic SCCHN is generally treated with chemotherapy alone and is not curable. Multiple chemotherapy agents have shown activity in this setting. Although combination regimens have shown superior improvement in responses compared with single agents, no randomized study has ever demonstrated an improvement in overall survival.
a. Methotrexate as a single agent (40 to 60 mg/m2 IV weekly) should be considered the standard of care because no other regimen had been shown to be superior.
b. Cisplatin/5-FU combination has been an acceptable standard largely due to an improved response rate. However, when tested in a randomized phase 3 trial versus single-agent methotrexate, despite an improved response rate (32% vs. 10%), no statistically significant difference was seen in survival (see Forastiere AA, Metch B, et al. in Selected Reading). Most practitioners reserve this regimen for younger, more fit patients who can tolerate cisplatin.
c. The roles of platin/5-FU and cetuximab
(1) The EXTREME trial was presented in June of 2007, which compared cisplatin (100 mg/m2 on day 1) or carboplatin (AUC 5 on day 1) plus 5-FU (1,000 mg/m2/day by continuous infusion on days 1 through 4), both with and without cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly). This study showed a significant improvement in median survival with the addition of cetuximab from 7 to 10 months. No crossover to cetuximab was allowed in the study.
(2) A randomized phase III trial by the Eastern Cooperative Oncology Group compared cisplatin and placebo with cisplatin and cetuximab in 117 eligible patients. The median and progression-free survivals were 8 and 3 months in the control group versus 9 months (P = 0.21) and 4 months (P = 0.07) in the experimental arm. Crossover was allowed in this study.
(3) Many investigators have interpreted the results of these important studies to mean that cetuximab should be used in the treatment of metastatic SCCHN. This is not necessarily so as the first-line regimen. For example, 5FU/cisplatin may be used as front line therapy with cetuximab used for second line. It is always appropriate, when available, to treat on a clinical trial, even if this means cetuximab is held until for second- or third-line treatment since the clinical studies do not clearly establish this agent for routine front line usage.
K. Adverse effects of treatment. All treatments of cancer, even when properly administered by current standards, may have unintended adverse consequences.
1. Radical surgery adverse effects depend on the primary site and the extent of ND
a. Interference with swallowing and/or speech
b. Loss or change in quality and forcefulness of voice
c. Aspiration pneumonitis
d. Shoulder or upper limb weakness as a result of resection of the spinal accessory nerve resulting in denervation of the trapezius muscle
e. Localized cutaneous sensory change or loss; injury to the cervical plexus can result in neuropathic pain and sensory loss in the anterolateral neck extending to the shoulder
f. Hypothyroidism
g. Diplopia, visual loss
h. Cosmetic deformities
2. Radiation therapy adverse effects depend on the radiation fields, dose, dose rate, technology, and whether chemotherapy is given concomitantly.
a. Acute, self-limiting effects
(1) Erythema of skin
(2) Conjunctivitis
(3) Mucositis in oral cavity, oropharynx, hypopharynx, nasopharynx, larynx, nasal fossa
(4) Alteration of taste
(5) Xerostomia, which may be minimized by total radiation dose reduction through use of techniques such as intensity modulated radiation therapy (IMRT). Medications, such as pilocarpine (Salagen), have been tried without scientifically documented success.
(6) Epilation (dose related) involving scalp, facial hair, eyelashes, eyebrows. Returning hair may be more sparse and even of a different color and texture.
(7) Edema; laryngeal edema is the most serious
(8) Lhermitte syndrome is an infrequent problem manifested as an “electric shock-like” sensation, usually in the upper limbs precipitated by flexion of the neck. This syndrome is secondary to radiation-induced change, probably temporary demyelination. It is not a precursor of permanent myelopathy.
(9) Infection, the most frequent of which is candidiasis controllable by fluconazole.
b. Long-term or permanent
(1) Xerostomia. Recovery from acute changes may be minimal with long-term adverse consequences, including tooth decay, oral infections, and problems swallowing and associated weight loss. Xerostomia also may be associated with autoimmune disorders (Sjögren syndrome), diabetes, scleroderma, and many medications, including antidepressants, antihypertensives, and medication for allergies.
(2) Altered taste: usually for salt or sweet
(3) Cataract: develops slowly (more frequent in diabetics)
(4) Osteoradionecrosis, usually of the mandible (worse with poor oral hygiene)
(5) Cervical myelopathy appears over several months and is permanent
(6) Soft tissue change: atrophy, telangiectasia, rarely ulceration
(7) Skin cancer: described in literature but is very rare
(8) Epilation
3. Chemotherapy as an adjunct can increase acute side effects of RT. The chemotherapeutic agents used for head and neck cancers will promote hematosuppression. The unique side effects of cisplatin and carboplatin are nephrotoxicity and neurotoxicity. The 5-fluorouracil commonly causes mucositis independent of RT, diarrhea, cardiotoxicity, and palmar–plantar erythrodysesthesia (the latter with infusional regimens). Taxanes can cause acute allergic reactions that usually can be prevented by pretreating with glucocorticoids, arthralgia/myalgia, and peripheral neuropathy.
4. Toxicity of CCRT. The addition of chemotherapy to RT increases toxicity of treatment, particularly mucositis. RTOG 91-11 compared CCRT with induction chemotherapy followed by RT and with RT alone. The incidence of grade 3 to 4 stomatitis was 73% in the CCRT arm and about 40% in the other two arms. At 1 year after treatment, the proportions of patients who could swallow only soft foods or liquids and who could not swallow at all were 23% and 3%, respectively, for CCRT; 15% and 3%, respectively, for RT alone; and 9% and 0%, respectively, for induction chemotherapy. No difference was noted in the three arms with regards to speech. Late grade 3 to 4 toxic effects were also reported to be 30% in the CCRT group compared with 36% in the RT only group. Treatment-related deaths were 5% in the CCRT compared with 3% in the induction chemotherapy and RT only arms.
L. Supportive care
1. Acute mucositis. Discomfort can be decreased by use of bland foods at room temperature, ice chips, topical analgesics or anesthetics, preparations (e.g., Ulcerease or Gelclair), and pain medications. The use of amifostine to decrease the incidence and severity of mucositis has been associated with inconsistent results; its use is also limited by the cost, side effects, and inconvenience of daily IV infusions of the drug. Mucositis is severe enough to require fastrostomy feeding tubes in about 50% of patients.
2. Opportunistic infections, most frequently candidiasis, can be controlled by specific medications.
3. Adequate nutrition is very important. Frequent meals, diet supplements, and high-calorie intake usually are adequate. Hyperalimentation is rarely used.
4. Dental care
a. All patients who plan to receive high-dose RT to the head and neck region, especially if major salivary glands are in the irradiated fields, should have dental consultation before the start of treatment.
b. Fluoride gel treatment should be used before, during, and after RT. Continuation of treatment should be based on consultation with the involved dentist.
c. Dentures should not be worn during treatment or until healing of the oral mucosa is complete (several months). Special dentures may be advisable.
d. Prophylactic tooth extraction may need to be performed before RT, and 1 to 2 weeks of recovery time may be necessary before any irradiation begins.
e. Special devices, such as intraoral shielding or bite opener, may need to be constructed by a specialty dentist before the RT planning session.
f. Chemotherapy can exacerbate significantly the dental sequelae of RT.
M. Special clinical problems
1. Local or regional regrowth of the previously treated cancer needs to be distinguished from the side effects of treatment. Cancer usually increases in mass and firmness and the overlying skin may become brawny, purple in color, and fixed to adjacent tissue. There may be associated ulceration. Although radiation side effects may persist or temporarily increase, usually there is tissue decrease with fibrosis and atrophy. Secondary radiation changes will be limited to the irradiated volume, whereas the regrowing cancer may extend outside the treatment volume. Biopsies of radiation-induced changes may be hazardous with the development of poorly or nonhealing ulceration and infection. Therefore, treatment, if potentially useful, usually can be instituted based on clinical appearance.
2. Cosmetic defects may be devastating to the patient. These usually are distortions such as secondary to seventh nerve palsy, reduction in size of the oral cavity, loss of portions of the nose or ear, loss or alteration of orbital contents, permanent absence of dentures, and unsightly grafts. Often reconstructive surgery is indicated. Psychological support is imperative. Interactions with support groups with similar problems may be useful.
3. Massive facial edema is an infrequent problem. The underlying cause is extensive venous or lymphatic obstruction secondary to uncontrolled cancer. Management is symptomatic and usually unsatisfactory. This usually is an end-stage problem with death secondary to cerebral edema, hemorrhage, or inanition.
4. Arterial rupture with rapid exsanguination owing to disruption of the carotid artery secondary to cancer or necrosis is a rare problem. Prevention is based on local tumor control, avoidance of progressive infection with necrosis, and proper technique of neck dissections.
5. Upper airway obstruction may be secondary to progressive cancer, edema, or a combination. The edema can be treated with high doses of prednisone (40 to 60 mg/day orally). Tracheostomy may bypass the obstruction and produce temporary relief. Associated infection should be vigorously treated. For patients who have tumor regrowth after irradiation, chemotherapy may provide tumor reduction.
6. Obstructive dysphagia. If this is secondary to progressive, previously treated cancer, there probably are accompanying adverse findings, such as airway obstruction and pain. Management usually accomplishes very little.
7. Infection associated with progressive, necrotic cancer can be treated with broad-spectrum antibiotics, although the effect usually is minimal and temporary.
N. Specific head and neck cancer sites. The relative occurrence, sex predominance, most common site, and histology of the constituents of head and neck cancers are compared in Table 7.2.
Table 7.2 Features of Head and Neck Cancers by Site of Origin
aAt least 97% are squamous cell carcinomas.
II. LIP
A. Definition. Cancers of the lip arise on the vermilion surfaces and mucosa. Cancers arising on the skin of the lower lip are considered separately as primary skin cancers.
B. Pathology. Nearly all lip cancers are squamous cell carcinomas, usually well differentiated.
C. Natural history
1. Presentation. Of primary lip cancers, 95% arise on the lower vermilion surface. This is probably due to the higher exposure of this lip owing to its anatomical position. The gross appearances range from minimal erythematous change, through dry-scaling to ulcerated masses, occasionally with destruction of underlying muscle and bone. The prognosis may be worse with a need for more aggressive treatment when the lateral commissure is involved by tumor.
2. Risk factors. Long-time exposure to sun or wind; chronic irritation.
3. Lymphatic drainage. From the upper lip primarily to the submandibular lymph nodes; from the lower lip to the submental, submandibular, and subdigastric nodes. The risk of metastases to regional lymph nodes increases with less differentiated tumors, large size, and extension of tumor to the lateral commissures. Of patients, 5% to 10% are likely to have spread to regional lymph nodes at the time of diagnosis and another 5% to 10% will develop adenopathy later.
D. Differential diagnosis
1. Keratoacanthoma is an exophytic lesion that arises rapidly and usually resolves spontaneously within a few months. Small doses of RT accelerate this resolution, but usually are not advisable.
2. Hyperkeratosis, often with irritation, infection, or both
3. Leukoplakia
4. Chancre when syphilis was more frequent
E. TNM staging and stage groups are shown in Table 7.1.
Primary tumor T1-T4 classification for lip cancers is as follows:
T1 Tumor ≤2 cm in greatest dimension
T2 Tumor >2 cm, but not >4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension
T4a Moderately advanced local disease: tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of chin or nose
T4b Very advanced local disease: tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery
F. Management of the primary cancer. Lip cancer, when detected early, can be cured equally well by limited surgery, RT, or chemosurgery (Moh method)
1. Vermilionectomy (lip shave) can be used to treat leukoplakia, severe dysplasia, and limited carcinoma in situ.
2. Tis and T1 carcinomas (≤1.0 cm). RT (external beam, isotope surface application, or implantation) or surgery (minimal resection with primary closure without reduction of oral stoma) are highly effective with good resulting cosmesis.
3. T1–4 carcinomas (>1.0 cm). RT has some cosmetic and functional advantages over surgery if no destruction of underlying normal tissues. If bone is involved or there is substantial loss of normal tissue, surgery with reconstruction is preferable.
4. Commissure involvement. RT has advantage over surgery.
5. Local tumor control rate. Failure rates are related to tumor size and extent. For the primary cancer, the failure rate is <10% for T1 lesions. Failure rate in the neck is <10% when the neck initially is N0 but may increase to 45% when there is gross metastatic adenopathy.
G. Treatment of regional lymph nodes
1. Clinically negative neck. Observation is preferable. RT can be used for primary cancers that are large or histologically poorly differentiated.
2. Clinically involved nodes. Surgery is preferable. When the primary cancer crosses the midline, both sides of the neck are at risk. The major adenopathy is best treated surgically. Subclinical tumor on the other side of the neck can be irradiated or treated with a limited neck dissection.
3. Delayed neck dissections can effectively treat metastatic adenopathy that appears clinically after previous treatment of the primary cancer.
H. Treatment of locally “reappearing” cancer can be effective. Surgery is preferable for the treatment of RT failures and additional resections can be used for surgical failures.
III. ORAL CAVITY
A. Definition. Includes primary cancers of the oral tongue, floor of the mouth, buccal mucosa (including the retromolar tigone), gingiva, alveolar ridge, hard palate, and anterior tonsillar pillar.
B. Pathology. Nearly all primary cancers are squamous cell carcinomas. Less than 5% are adenocarcinomas (adenoid cystic, mucoepidermoid carcinomas arising from minor salivary glands).
C. Natural history
1. Risk factors include use of tobacco products, long-time ingestion of alcoholic beverages, poor oral hygiene, and prolonged focal irritation from teeth or dentures.
2. Presentation
a. Patients with oral tongue cancers may notice a local mucosal irritation or a mass that may become ulcerated, infected, and painful. A foul odor or taste may be associated with infection. Pain may be local or referred to the ear. Infiltration of muscle can give rise to problems transporting boluses or speaking.
b. Early buccal mucosa cancers may be asymptomatic or felt by the tongue. Ulceration can result in local pain. Obstruction of Stensen duct may be the basis of tender enlargement of the parotid gland. Pain referred to the ear follows tumor involvement of the lingual or dental nerves. Local tumor extension can cause trismus.
c. Gingival cancers may be noted as local mucosal changes, often with accompanying leukoplakia. More extensive cancers cause loosening of teeth, interference with denture use, bleeding, or pain. Underlying bone may be invaded. Tumor may extend to involve adjacent anatomic structures, such as floor of mouth, buccal mucosa, hard and soft palate, or maxillary sinus.
d. Cancers of the retromolar trigone can cause trismus by involving the pterygomandibular space, pterygoid, and buccinator muscles.
e. Cancers arising on the hard palate are likely to invade bone.
f. Cancers arising from the mucosa of the floor of the mouth may be seen as a localized mucosal change, often with leukoplakia, or felt as a mass by the patient. When localized with ulceration and tenderness, these lesions initially may be misdiagnosed as canker sores. With local extension, there may be a submandibular mass, obstruction of the submaxillary ducts with gland enlargement, and invasion of the oral tongue or mandible.
3. Lymphatic metastases most often involve subdigastric, upper jugular, and submandibular nodes. The frequency varies with site, extent, and differentiation of the primary cancer, but may range up to 30% to 35% at the time of diagnosis with a later increase in untreated necks secondary to the growth of initial subclinical metastases. The risk of bilateral metastases increases as the primary tumor approaches or involves the anatomic midline.
4. Metastases below (caudad) the clavicles or above (cephalad) the base of the skull are infrequent, whether lymphatic or hematogenous.
D. Diagnosis. Establishment of a diagnosis of cancer arising in the oral cavity should be relatively straightforward because patients usually have distinctive symptoms and signs and the tumors can easily be visualized and palpated. A diagnosis must be established by biopsy. Imaging examinations (CT, MRI) have become a major part of the appraisal of tumor extent, bone involvement, and lymph node metastases.
E. TNM staging and stage groups are shown in Table 7.1.
Primary tumor T1-T4 classification for oral cavity cancers is as follows:
T1 Tumor ≤2 cm in greatest dimension
T2 Tumor >2 cm, but not >4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension
T4a Moderately advanced local disease: tumor invades adjacent structures only (e.g., through cortical bone [mandible or maxilla] into deep [extrinsic] muscle of tongue [genioglossus, hypoglossus, palatoglossus, and styloglossus], maxillary sinus, or skin of face). Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify tumor as T4.
T4b Very advanced local disease: tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery
F. Management of the primary tumor
1. Oral tongue and floor of mouth carcinomas
a. Small tumors (<1.0 cm). Resection with primary closure; interstitial RT; or external beam RT using oral cone (rarely used)
b. T1 or T2 tumors. Resection if minimal deformity or combination of external beam RT and intersitial RT. The choice can vary with patient preference, health status, and occupational, social, or psychological factors.
c. Extensive tumors. Resection followed by external beam RT. Surgery is preferable when the mandible is invaded by tumor, and for verrucous carcinomas and unreliable patients.
d. Local tumor control rate with RT (approximate)
T1 tumors, 80%
T2 tumors, 65% to 70%
T3 tumors, 25%
2. Gingival and hard palate carcinomas
a. Small tumors. Resection
b. Extensive tumors. Resection and postoperative RT
c. Local control rate of T1 tumors. 60%
3. Buccal mucosal carcinomas
a. Small tumors (<1.0 cm). Resection and primary closure
b. T1–3. RT or resection, probably with a graft
c. Larger superficial cancers (T1–2). RT effective
d. Extensive tumors (T3–4) with invasion of muscle. Resection and postoperative RT
e. Tumor extension to commissure. RT should be considered
f. Local tumor control rate with RT (approximate)
T1 tumors, >95%
T2 tumors, 70%
T3 tumors, 70%
T4 tumors, 50%
4. Retromolar trigone. (faucial pillar carcinomas)
a. T1–2 tumors. RT or resection with or without RT
b. T3 superficial tumors. RT
c. Large tumors, deep infiltration. Resection and postoperative RT (special problems exist with extension of tumor into the pharyngeal tongue or bone)
d. Local tumor control rate
T1 tumors, 75%
T2 tumors, 70% to 75%
T3 tumors, 70% to 75%
5. Management of the neck. When the primary cancer is controlled, death caused by uncontrolled metastatic cancer in the neck should be uncommon. The risk of subclinical involvement of neck nodes is related to the T stage and histologic differentiation. Although adenopathy usually can be treated successfully after observation of an N0 neck, elective treatment may lessen the risk of uncontrolled tumor in the neck and development of distant metastases. Some general guidelines are as follows:
a. Clinically “negative” neck
(1) T1, low-grade primary cancers. Observation if the patient is reliable
(2) T2–4 or poorly differentiated primary cancers
(a) If the primary tumor is treated surgically, perform elective neck dissection.
(b) If the primary cancer is irradiated, the neck should be concurrently irradiated.
(c) If the primary cancer is managed by combined treatment methods, either treatment method may be used.
b. Clinical lymphadenopathy
(1) If the primary tumor is treated surgically, add ND.
(2) If the primary tumor is treated with RT, irradiate the neck and follow with ND for residual adenopathy after adequate observation or if an initially enlarged node was large (i.e., >3.0 cm).
(3) When the tumor-involved nodes are “fixed,” start with RT. If the adenopathy becomes resectable, perform ND after about 5,000 cGy. If not, give RT to full total dose.
IV. OROPHARYNX
A. Definition. Includes pharyngeal (“base of”) tongue, tonsillar region (fossa and pillars although anterior pillar often included in oral cavity), soft palate, and pharyngeal walls between the pharyngoepiglottic fold and the nasopharynx.
B. Pathology. Ninety-five percent are squamous cell carcinomas, usually less histologically differentiated than those of the oral cavity. A few tumors may be adenocarcinomas arising in the minor salivary glands or primary lymphomas.
C. Natural history
1. The role of HPV. Risk factors for oropharyngeal carcinoma include prolonged consumption of tobacco products and alcoholic beverages, especially for primary carcinomas of the anterior tonsillar pillar and posterior pharyngeal wall. However, HPV has for some time been suggested to be involved in its carcinogenesis. The Agency for Research on Cancer (IARC) now recognizes HPV as an additional risk factor for oropharyngeal cancer, and accumulating molecular and epidemiologic data now show that high-risk types of HPV (predominantly HPV-16) are responsible for a subset of oropharyngeal cancer. HPV-positive cancer cases are now in majority in the Western world, and these tumours are also shown to have better outcome than the HPV-negative patients. This prognostic difference has not been confirmed in nonoropharyngeal cancers with respect to HPV status.
According to a workshop hosted by The Cancer Etiology Branch of the National Cancer Institute entitled “Validation of a Causal Relationship: Criteria to Establish Etiology,” four types of evidence are necessary to establish a causal relationship in cancer: epidemiologic, molecular pathologic, experimental, and evidence derived from animal studies. There is strong epidemiologic and molecular pathology evidence indicating that HPV-16 is associated with oropharyngeal cancers.
In addition, it has become clear that HPV-positive oropharyngeal cancer is defined by unique patient demographics and disease characteristics. The cancers are increasing in incidence and are almost exclusively confined to the palatine tonsil and base-of-tongue. HPV-positive patients tend to be younger and have less exposure to tobacco and alcohol. The cancers tend to present with lower T-stage and higher N-stage and have been strongly epidemiologically linked with sexual activity, especially oral sex.
For HPV DNA+ patients overall survival (OS) and progression-free survival are substantially better [OS, P < 0.0001] and local regional failures are less frequent (P = 0.0006). At 5 years, 82% of HPV DNA+ patients were alive as opposed to 35% of HPV-negative patients (P < 0.0001).
One potential explanation for these different outcomes is that HPV-associated cancer is inherently less aggressive than tobacco-induced cancer. The conclusion across studies is that HPV-associated cancer has a favorable outcome independent of treatment selection, as long as treatment is within the current standard of care. For example, it has been shown that even when surgery is the only treatment modality used, oropharyngeal cancer patients with HPV-positive tumors have a better prognosis than those with HPV-negative tumors, after adjustment for tumor stage. Another hypothesis is that molecular features of HPV-positive tumors may contribute to their better response to treatment with radiation and chemotherapy. At the molecular level, it has been shown that p53 and pRb tumor suppressor pathways in HPV-positive cancer cells are active but dormant. Other gene and protein expression differences might also explain the different clinical behaviors.
Given the improved prognosis for patients with HPV-related oropharyngeal cancers, it is speculated that perhaps less intense therapy may be adequate to maintain the high survival rate seen with traditional intense therapy. Studies are ongoing to test this hypothesis.
2. Clinical presentation
a. May be clinically “silent,” especially those cancers arising in the pharyngeal tongue where the tumor may be submucosal, but indurated.
b. Pharyngeal tongue and tonsillar carcinomas may appear clinically as cervical adenopathy.
c. Symptoms include localized pain aggravated by swallowing, ipsilateral otalgia, difficulty swallowing secondary to pain, or decreased mobility of the tongue. The patient may feel a mass at the primary site or in the neck.
3. Lymphatic drainage. The lymphatics of the pharyngeal tongue, tonsil, and pharyngeal wall are abundant. The lymphatics of the pharyngeal tongue drain into the deep cervical nodes and involvement often is bilateral. The lymphatics of the tonsillar region and faucial arch drain into the subdigastric, upper and middle cervical, and parapharyngeal nodes. Metastases usually are ipsi-lateral unless the primary tumor approaches the midline. Lymphatic drainage from the pharyngeal wall is to the retropharyngeal and level II–III cervical nodes.
D. Diagnosis. Cancers arising in the oropharynx can be visualized and palpated. The diagnosis must be documented by biopsy. Differential diagnoses on physical examination include tonsillar abscess, benign lymphoid hyperplasia, and benign ulceration with induration.
E. TNM staging. Clinical staging often is used because many of these cancers are treated by primary RT. Assessment for clinical staging is based on inspection, palpation, CT, and MRI examination. Pathologic staging adds information found at surgery.
TNM staging and stage groups are shown in Table 7.1. Primary tumor T1–T4 classification for cancers of the oropharynx is as follows:
T1 Tumor ≤2 cm in greatest dimension
T2 Tumor >2 cm, but not >4 cm in greatest dimension
T3 Tumor >4 cm in greatest dimension or extension to lingual surface of epiglottis
T4a Moderately advanced local disease: tumor invades the larynx, extrinsic muscle of the tongue, medial pterygoid, hard palate or mandible. Mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of larynx.
T4b Very advanced local disease: tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery.
F. Management of the primary tumor
1. Pharyngeal tongue
a. Small tumors. Surgery if lateralized or RT
b. Larger tumors. Especially if approaching midline, RT
c. Local tumor control
T1 tumors, 85% to 90%
T2 tumors, 75%
T3 tumors, 65%
2. Tonisllar region
a. Small tumors. Surgery or RT
b. Extensive primary tumors. Surgery plus postoperative RT
c. Local tumor control
T1 tumors, 95%
T2 tumors, 85%
T3 tumors, 50%
T4 tumors, 20%
3. Soft palate
a. Small tumors. Usually RT or surgery if minimal resulting dysfunction
b. Large tumors. RT
c. Local tumor control
T1 tumors, 95%
T2 tumors, 65% to 90%
T3 tumors, 50% to 75%
T4 tumors, 20%
4. Pharyngeal wall
a. Small tumors. RT can be effective with minimal morbidity
b. Extensive tumors. RT and surgery if applicable
c. Local tumor control rate for T2–3 tumors. 35% to 50%
G. Management of the neck. Primary carcinomas arising in the pharyngeal tongue, soft palate, and pharyngeal wall are likely to metastasize to nodes in both sides of the neck. Limited primary cancers of the tonsillar region may metastasize only to ipsilateral nodes.
For primary carcinomas managed by RT, the neck should be part of the initial treatment plan. As the cervical adenopathy becomes larger or more nodes are involved, ND becomes part of the management. If the initial treatment of the primary site and the neck is surgery, postoperative RT is advisable when the primary tumor is extensive, the histology is poorly differentiated, the adenopathy is large (i.e., >3.0 cm), multiple nodes are involved, or when tumor extends through the capsule of the node. CCRT may also be considered under these circumstances.
H. Treatment of “recurrence.” Repeated thorough examinations at intervals of a few months are an important part of patient management. Most persistence or regrowth of tumor can be recognized within 2 years of treatment of the initial cancer. Salvage treatment by either surgery or RT or both may be successful. These patients are also at high risk to develop other cancers.
V. NASOPHARYNX
A. Definition. Carcinomas of the nasopharynx arise in a small anatomic site bordered by the nasal fossae, the posterior wall continuous with the posterior wall of the oropharynx (first and second cervical vertebrae), the body of the sphenoid and basilar part of the occipital bones, and the soft palate.
B. Pathology. About 90% of malignant tumors are squamous cell carcinoma, whereas 5% are lymphomas and 5% are of other various subtypes. The squamous cell carcinomas are 20% well-differentiated, 40% to 50% moderately differentiated, and 40% to 50% undifferentiated (lymphoepitheliomas).
C. Natural history
1. Risk factors
a. Incidence higher in Asians, particularly those from southern China, Eskimos, and Icelanders. This risk prevails in first generation immigrants to other parts of the world.
b. Nonkeratinizing nasopharyngeal carcinomas are uniformly associated with Epstein–Barr virus (EBV); patients usually have increased levels of immunoglobulin A antibody to the viral capsid antigen and early antigen. Monitoring EBV DNA in the serum of affected patients using real-time polymerase chain reaction technology appears to be useful tool for gauging responses to therapy.
c. Can occur in the pediatric age group.
2. Presentation
a. Often initially noted as high posterior cervical adenopathy, which may be bilateral
b. Epistaxis, nasal obstruction
c. Change in voice
d. Unilateral hearing loss or “fullness” in one ear, serous otitis
e. Trismus
f. Headache
g. Proptosis
h. Cranial nerve syndromes secondary to tumor invasion of base of skull
(1) Retrosphenoidal syndrome from involvement of cranial nerves II through VI manifests as unilateral ophthalmoplegia, ptosis, pain, trigeminal neuralgia, and unilateral weakness of muscles of mastication.
(2) Retroparotid syndrome from compression of cranial nerves IX through XII and sympathetic nerves manifests as mechanical dysphagia, problems with taste, salivation, or respiration, weakness of the trapezius, sternocleidomastoid muscles, or tongue muscles, and Horner syndrome.
i. Distant metastases more frequent with nasopharyngeal carcinoma than with any other head and neck cancer
3. Lymphatic drainage. The abundant lymphatics drain to the retropharyngeal and deep cervical lymph nodes (internal jugular and spinal accessory nerve chains). Drainage is bilateral. Lymphadenopathy is present in 80% of patients at presentation with 50% being bilateral.
4. Prognostic factors
a. Tumor extent, particularly invasion of the base of the skull
b. Size and level of cervical node metastases
c. Age (prognosis is better with age <40 to 50 years)
d. Tumor type
D. Diagnosis
1. Endoscopy to identify the primary cancer, which may be a minimal mucosal alteration or mass
2. Palpation of the neck for adenopathy, which usually is high posterior cervical and often is bilateral
3. CT or MRI to identify the extent of primary tumor and adenopathy and involvement of the base of the skull
4. Cranial nerve examination
5. Differential diagnoses include benign adenopathy of Waldeyer ring, nasopharyngitis, and cervical adenopathy of other etiology.
E. TNM staging for nasopharyngeal carcinoma differs from that of other head and neck cancers. Definitions of classification and stage groups for nasopharyngeal tumors according to the 7th edition of the AJCC Cancer Staging Manual (2010) are as follows:
Primary tumor (T)
T1 Tumor confined to nasopharynx, or tumor extends to oropharynx and/or nasal cavity without parapharyngeal extension
T2 Tumor with parapharyngeal extension (posterolateral infiltration of tumor)
T3 Tumor invades bony structures of skull base and/or paranasal sinuses
T4 Tumor with intracranial extension and/or involvement of cranial nerves, hypopharynx, orbit or with extension to the infratemporal fossa/masticator space
Regional lymph nodes (N) [note: midline nodes are considered ipsilateral nodes]
Nx Cannot be assessed
N0 No metastasis to regional nodes
N1 Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral retropharyngeal lymph nodes ≤6 cm in greatest dimension
N2 Bilateral metastasis in cervical lymph nodes ≤6 cm in greatest dimension, above the supraclavicular fossa
N3a Metastasis >6 cm in greatest dimension
N3b Extension to supraclavicular fossa
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Stage groupings
0 T is N0 M0
I T1 N0 M0
II T1,2 N1 M0; T2 N0 M0
III T1–3 N2 M0; T3 N0,1 M0
IVA T4 Any N M0
IVB Any T N3 M0
IVC Any T Any N M1
F. Management of the primary tumor. Surgery usually is not applicable because tumor-free margins cannot be obtained at the base of the skull. RT with high-energy x-rays, often combined with chemotherapy, is the treatment of choice.
1. Local tumor control rate at 5 years after initial treatment can be related to T stage
T1 90%
T2 80%
T3 70%
T4 50%
2. Treatment sequelae may be severe after RT with the necessary high total doses. These include local ulceration, occasionally with necrosis, retinopathy, fibrosis of soft tissues in the neck, and middle ear changes. These sequelae can be reduced with modern treatment planning.
G. Management of regional lymph nodes. External beam RT is the choice because the adenopathy frequently is bilateral in the neck and often involves the retropharyngeal lymph nodes. Control of regional adenopathy also is related to N stage but has not been well documented. Neck dissection may be useful for tumor that persists or regrows after primary irradiation.
H. Chemotherapy for nasopharyngeal carcinoma. About 60% of patients have stage III or IV disease and often develop distant metastases. Induction chemotherapy has resulted in high response rates, but no change in overall survival and is not recommended. CCRT involving cisplatin with or without 5-FU (see Section I.J.3.) for three cycles is considered standard therapy in the Western world. CCRT appears to double the 5-year survival rate to 67%, but about half of the patients cannot complete planned therapy because of toxicity.
I. Treatment of local recurrence. Retreatment is more often successful for nasopharyngeal carcinoma than after failure of treatment of other head and neck cancers. Reirradiation of the primary tumor site still requires a high total dose, and may be done with precision-oriented external beam treatment, such as intensity modulated RT (IMRT) or brachytherapy. Limited post-RT failures in the neck may be controlled by surgery.
VI. HYPOPHARYNX
A. Definition. The “low pharynx” is between the level of the hyoid bone and the entry to the esophagus at the level of the lower border of the cricoid cartilage. It contains the piriform sinuses, aryepiglottic folds, postcricoid region, and lateral pharyngeal walls.
B. Pathology. Of malignant tumors, >95% are squamous cell carcinomas. Histologic differentiation varies with the anatomic site. For example, squamous cell carcinomas of the aryepiglottic fold are twice as likely to be well differentiated as are tumors arising in the piriform sinus.
C. Natural history
1. Risk factors
a. Use of tobacco and alcoholic beverages
b. Having had other cancers in the aerodigestive tract
c. Women more likely to develop postcricoid carcinomas than are men
2. Clinical presentation
a. May be asymptomatic and notice mass in the neck
b. Pain aggravated by swallowing
c. Blood-streaked saliva
d. Mechanical dysphagia
e. Ear pain
f. Voice change
g. Aspiration with pneumonia
h. Cervical adenopathy in >50% (in 25%, a mass in the neck will be the initial finding)
3. Lymphatic drainage
a. Extensive lymphatics with frequent metastases to midcervical chain (jugulodigastric nodes may be first affected), posterior cervical triangle and paratracheal lymph nodes.
b. Frequency of metastases to cervical nodes related to primary tumor site and extent
(1) Piriform sinus. 60%
(2) Aryepiglottic fold. 55%
(3) Pharyngeal wall. 75%
4. Prognostic factors
a. Anatomic site and extent of primary tumor
b. Cervical node metastases
c. Distant metastases (20% at diagnosis)
D. Diagnosis. These cancers usually are locally advanced at diagnosis.
1. History and physical examination to include palpation and direct and indirect laryngoscopy
2. CT and MRI are essential to determine extent of primary tumor and cervical node metastases
E. TNM staging. TNM staging and stage groups are shown in Table 7.1. Primary tumor T1–T4 classification for cancers of the hypopharynx is as follows:
T1 Tumor limited to one subsite of hypopharynx and measuring ≤2.0 cm in greatest dimension
T2 Tumor invades more than one subsite of hypopharynx or an adjacent site, or measures >2.0 cm but not >4.0 cm in greatest dimension without fixation of the hemilarynx
T3 Tumor >4 cm in largest dimension or with fixation of the hemilarynx or extension to esophagus
T4a Moderately advanced local disease: tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue (includes prelaryngeal strap muscles and subcutaneous fat)
T4b Very advanced local disease: tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures
F. Management of the primary tumor
1. Piriform sinus
a. T1 and some T2 tumors. RT might be preferable. Partial laryngopharyngectomy with neck dissection is effective but with greater morbidity.
b. Advanced carcinoma extending into apex or outside piriform sinus often with invasion of larynx, thyroid cartilage, soft tissues of neck. Total laryngopharyngectomy, radical ND, and postoperative RT. If resection not possible, RT for palliation.
c. Local tumor control rate
T1–2 65% to 80%
T3–4 50%
2. Aryepiglottis
a. T1–2 tumors. RT or supraglottic resection
b. T3–4 tumors. Surgery with laryngeal conservation if possible, followed by RT
c. Local tumor control rate for T1–2 tumors. 90%.
3. Hypopharyngeal walls
a. RT or resection with unilateral neck dissection plus postoperative RT
b. Local tumor control rate
T1 90%
T2 70%
T3 60%
T4 35%
4. Management of local recurrence at the primary site. RT if patient only had surgery; further RT is not effective in previously irradiated patients.
G. Management of the neck
1. No clinical adenopathy. RT to primary site and neck, with or without planned ND
2. Clinical cervical node metastases. RT plus planned ND
3. Management of recurrence in the neck. ND if failure of RT, or RT if failure of ND. The patient, however, often has already had both ND and RT.
VII. LARYNX
A. Definition. Laryngeal cancer involves three anatomic sites
1. Glottis—paired true vocal cords
2. Supraglottis—epiglottis, false vocal cords, ventricles, aryepiglottic folds (laryngeal surface), arytenoids
3. Subglottis—arbitrarily begins 5.0 mm below free margin of true vocal cord and extends to inferior border of cricoid cartilage
B. Pathology. Of malignant tumors arising from the epithelium, >95% are squamous cell carcinomas. The remainders are sarcomas, adenocarcinomas, and neuroendocrine tumors.
C. Natural history
1. Risk factors
a. Use of tobacco
b. Prior occurrence of other carcinomas of aerodigestive tract
c. A possible relationship between gastroesophageal reflux disease (GERD) and glottic cancer has been observed.
2. Presentation
a. Vocal cord. Persistent hoarseness
b. Supraglottis. Often no symptoms; sore throat; intolerance to hot or cold food; ear pain
c. Subglottis. Usually no symptoms until locally extensive
3. Lymphatic drainage
a. True vocal cords. None (the true vocal cords are devoid of lymphatics)
b. Supraglottis. Rich network draining to subdigastric and midinternal jugular nodes
c. Subglottis. Sparse network draining to inferior jugular nodes
D. Diagnosis
1. Palpation of neck for cervical adenopathy and laryngeal crepitus
2. Endoscopy
3. CT and MRI to assess site and extent of primary tumor and cervical adenopathy
E. TNM staging and stage groups are shown in Table 7.1. Primary tumor T1–T4 classification for cancers of the larynx is as follows:
1. Supraglottis
T1 Tumor limited to one subsite of the supraglottis; normal vocal cord mobility
T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus); normal vocal cord mobility
T3 Tumor limited to larynx with vocal cord fixation and/or invasion of postcricoid area, pre-epiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage
T4a Moderately advanced local disease: tumor invades through thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus)
T4b Very advanced local disease: tumor invades prevertebral space or mediastinal structures, or encases carotid artery
2. Glottis
T1 Tumor limited to vocal cord(s) with normal mobility; may involve anterior or posterior commissure
T1a Tumor limited to one vocal cord
T1b Tumor involves both vocal cords
T2 Tumor extends to supraglottis and/or subglottis and/or with impaired vocal cord mobility
T3 Tumor limited to larynx with vocal cord fixation and/or invasion of the paraglottic space, and/or inner cortex of the thyroid cartilage
T4a Moderately advanced local disease: Same as supraglottis
T4b Very advanced local disease: Same as supraglottis
3. Subglottis
T1 Tumor limited to subglottis
T2 Tumor extends to vocal cord(s) with normal or impaired mobility
T3 Tumor limited to larynx with vocal cord fixation
T4a Moderately advanced local disease: Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus)
T4b Very advanced local disease: Same as supraglottis
F. Management of the primary tumor
1. Principles. After the initial objective of tumor control with preservation of the patient’s life, preservation of voice and the swallowing reflex become of major importance. RT alone or limited surgery can accomplish these objective in many laryngeal cancers.
a. Partial laryngectomy for selected situations may result in tumor control and preservation of a useful voice.
b. Salvage (total) laryngectomy may be successful after failure of conservative treatment.
c. Locally extensive cancers, especially with edema, usually require total laryngectomy often followed by RT.
d. Chemotherapy. Induction chemotherapy followed by definitive RT achieves laryngeal preservation in a high percentage of patients with advanced cancer, but does not improve overall survival. CCRT (Section I.J.3.) has been more successful for both laryngeal preservation and survival than induction chemotherapy, however, and is recommended as the treatment of choice for locally extensive cancers. High total radiation doses with modern techniques, such as IMRT, conformal planning, accelerated fractionation, and hyperfractionation, may be comparably successful.
e. Sequelae of treatment
(1) RT. Edema, usually temporary, and chondritis, which is rare; infrequent persistent minimal voice change
(2) Partial laryngectomy. Some voice deterioration, interference with swallowing reflex
(3) Total laryngectomy. Loss of voice; >50% of patients can develop effective speech with a prosthesis (speaking fistula)
2. True vocal cords including anterior or posterior commissures
a. Tis. RT or “cord stripping”
b. T1–2. RT preferable; cordectomy and vertical hemilaryngectomy have more sequelae
c. T3, limited tumors. May respond to RT, surgical salvage can follow
d. T3, extensive tumors. Surgery, usually followed by RT; or CCRT
e. T4. Total laryngectomy and postoperative RT; or CCRT for larynx preservation
f. Persistent or recurrent cancer
(1) Surgery for RT failure
(2) RT or more extensive surgery or both for failure of limited surgery
(3) RT for failure after total laryngectomy
g. Local tumor control rates
(1) T1. 90% to 95% with RT and most failures can be salvaged surgically; voice preservation in 95%
(2) T2. 75% to 80% with RT and most failures can be salvaged by surgery; voice preservation in 80% to 85%
(3) T3. favorable tumors with minimal fixation of vocal cords. 60% by RT increased to 85% by salvage surgery
(4) T3 more extensive tumors. 40% with RT, increased to 60% by salvage surgery; total laryngectomy—55% to 70%
(5) T4a favorable with early invasion of thyroid cartilage. 65% with RT; extensive with involvement of piriform sinus 20% with RT; laryngectomy, 40% to 50%
3. Supraglottic carcinoma
a. T1–2. RT or supraglottic laryngectomy
b. T3. RT often controls exophytic tumors; surgery can be reserved for salvage; for infiltrating tumors, surgery is preferable often with postoperative RT
c. T4. Surgery followed by postoperative RT. In a group of medically inoperable patients, RT resulted in a 35% local tumor control.
d. Local tumor control rate
T1 95% to 100%
T2 80% to 85%
T3 65% to 75%
T4 <50%
e. Treatment of recurrent cancer
(1) Surgery for RT failures
(2) RT for surgery failures
(3) Chemotherapy
4. Subglottic carcinoma
a. Usually extensive when discovered; treat with surgery + RT
b. Local tumor control <25%
G. Management of the neck
1. Glottic carcinomas. When tumor limited to true vocal cords, there are no metastases to be treated.
2. Extensive glottic tumors and supraglottic carcinomas. The neck can initially be managed by the method used for treatment of the primary tumor. Persistent adenopathy after primary RT should be treated surgically. Surgical failures can be irradiated.
VIII. NASAL CAVITY AND PARANASAL SINUSES
A. Definition. Knowledge of the complex anatomy is basic to understanding these tumors. The nasal vestibule is the entrance to the nasal fossa. It is bounded by the columella, nasal ala, and floor of the nasal cavity. The nasal fossa extends from the vestibule to the choana posteriorly, communicating with the nasopharynx, paranasal sinuses, lacrinal sac, and conjunctiva. The boundaries of the maxillary sinus are the orbit, lateral wall of the nasal fossa, hard palate (the roots of the first two molar teeth may project into the floor), infratemporal fossa, and pterygoplatine fossa. The multiple ethmoidal sinuses are in the ethmoid bone between the nasal cavity and orbit. The left and right frontal sinuses in the frontal bone are separated by a septum. The dual sphenoid sinuses are surrounded by the pituitary fossa, cavernous sinuses, ethmoidal sinuses, nasopharynx, and nasal cavities.
B. Pathology
1. Nasal vestibule. Nearly all are squamous cell carcinomas; a few are basal cell or adnexal carcinomas; <1% are melanomas.
2. Nasal cavity and paranasal sinuses. Most are squamous cell carcinomas; 10% to 15% arise in minor salivary glands; 5% are lymphomas. Other tumors include chondrosarcoma, osteosarcoma, Ewing tumor, giant cell tumor of the bone.
3. Esthesioneuroblastomas arise from neuroepithelium. (See Chapter 19, Section VII.)
4. Inverting papilloma
5. Midline lethal granuloma (extranodal NK/T-cell lymphoma, nasal type)
C. Natural history
1. Risk factors. Causes are unknown, but carcinoma is more frequent in workers exposed to nickel or wood dust and, historically, in patients exposed to radioactive thorium as an x-ray contrast agent.
2. Presentation
a. Nasal vestibule. Small, crusted plaques, ulceration, bleeding
b. Nasal fossa. Unilateral discharge, bleeding, obstruction
c. Maxillary sinus. Findings may mimic inflammation; pain, upper dental problems, proptosis
d. Ethmoid sinuses. Anatomic distortion, pain, local extension
e. Sphenoid sinus. Ill-defined headache, neuropathy of cranial nerves III, IV, V, and VI
3. Lymphatic drainage
a. Nasal fossa, ethmoidal and frontal sinuses—to submaxillary nodes; to nodes at base of skull when olfactory region involved
b. Maxillary sinus—to ipsilateral subdigastric and submandibular nodes
c. Sphenoid sinus—to jugulodigastric nodes
4. Prognostic factors
a. Anatomic site (i.e., cancers of nasal fossa nearly always are cured, whereas cancers of the sphenoid sinus are rarely controlled)
b. Tumor extent
c. Patients’ general health (treatment usually is demanding)
D. Diagnosis
1. Clinical symptoms and signs
2. Direct visualization of nasal vestibule and fossa, palate, alveolar ridge, external orbit (proptosis)
3. Endoscopy of nasopharynx for tumor extension
4. Cranial nerve evaluation
5. MRI and CT examinations of primary site and neck
6. Differential diagnoses
a. Nasal polyps (inverting papillomas)
b. Inflammatory disease
c. Upper dental problems
d. Destructive mucoceles
E. TNM staging. The AJCC staging system is limited to the maxillary and ethmoidal sinuses and excludes nonepithelial tumors. Clinical staging includes inspection, palpation; examination of orbits, nasal and oral cavities, nasopharynx, and of cranial nerves; MRI and CT. Pathologic staging includes clinical data plus information from the surgical specimen and the surgeon’s observations.
TNM staging and stage groups are shown in Table 7.1. Primary tumor T1–T4 classification for cancers of the nasal cavity and paranasal sinuses is as follows:
1. Maxillary sinus
T1 Tumor limited to maxillary sinus mucosa without erosion or destruction of bone
T2 Tumor causing bone erosion or destruction (except for posterior wall of maxillary sinus and pterygoid plates), including extension into hard palate and/or middle nasal meatus
T3 Tumor invading any of the following: bone of the posterior wall of the maxillary sinus, subcutaneous tissues, floor or medial wall of orbit, infratemporal fossa, pterygoid plates, or ethmoid sinuses
T4a Moderately advanced local disease: tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plates, sphenoid sinus, or frontal sinuses
T4b Very advanced local disease: tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve (V2), nasopharynx, or clivus
2. Nasal cavity and ethmoid sinus
T1 Tumor confined to any one subsite, with or without bony invasion
T2 Tumor invades two subsites in a single region or extends to involve an adjacent region within the nasoethmoidal complex, with or without bony invasion.
T3 Tumor invades the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate.
T4a Moderately advanced local disease: Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid, or frontal sinuses.
T4b Very advanced local disease: Same as maxillary sinus.
3. Nasal vestibule. Same as for skin of face.
F. Management of primary tumors
1. Nasal vestibule
a. Small tumors. RT if surgery will produce deformity; chemosurgery or laser surgery
b. Large tumors. RT or surgery + RT (plastic surgery repair if possible)
c. Persistence of tumor. Surgery for RT failures; more extensive surgery or RT for surgery failures; chemosurgery, laser surgery
2. Nasal fossa
a. Small tumors. RT if surgery will produce deformity; surgery with or without RT if bone involved
b. Large tumors. Combined surgery and RT; RT for lymphomas and melanomas
c. Esthesioneuroblastomas. Probably combined surgery and RT; chemotherapy (i.e., cisplatin + etoposide) may be helpful
3. Maxillary sinus. Fenestration of the palate allows direct inspection and access for biopsy and drainage
a. Small tumors. Surgery alone except for infrequent highly radiation responsive tumors such as lymphomas
b. Advanced tumors. Surgery and postoperative RT; chemotherapy and radiotherapy may be used preoperatively in an attempt to make resection possible
c. Unresectable tumors. RT and chemotherapy
d. Local treatment failure. Usually all modalities have been used; trial of chemotherapy, cautery, or cryosurgery
4. Ethmoid sinus
a. Limited lesions. Surgery
b. Most tumors. Surgery and postoperative RT
5. Sphenoid sinus. RT, possibly with chemotherapy (nearly always extensive when recognized)
6. Local tumor control rates
a. Nasal vestibule. Most tumors are small and nearly 100% controlled
b. Nasal fossa. Stage I, nearly 100%; control decreases with increasing extent
c. Esthesioneuroblastoma. 90% for Kadish stage A tumors
d. Ethmoid sinuses. Approximately 60%
e. Maxillary sinus. 75% to 80%
f. Sphenoid sinuses. Usually extensive when discovered with very infrequent local tumor control
G. Management of the neck
1. Nasal vestibule. Small tumors; observation with ND if adenopathy develops
2. Nasal fossa. Observation and ND if adenopathy develops (for tumors <5 cm, <10% ever develop adenopathy)
3. Esthesioneuroblastoma. ND, usually as part of primary surgery
4. Maxillary sinus. ND, usually as part of primary surgery
H. Treatment of local recurrence
1. Small tumors may be salvaged by surgery after RT failures or additional surgery after failure of initial surgery
2. Extensive tumors usually have received both surgery and RT and retreatment usually not feasible; palliative chemotherapy
IX. MAJOR SALIVARY GLANDS
A. Definitions
1. Major salivary glands. Parotid, submandibular, sublingual
2. Minor salivary glands. Widespread in mucosa of upper aerodigestive tract
B. Pathology. A range of histologic tumor types arise from ductal and acinar cells of the epithelium. The most frequently involved site is the parotid gland with tumors being 10-fold more frequent than in the submaxillary or minor salivary glands. The histologic subtypes and approximate frequencies are
Mucoepidermoid, 35%
Adenocarcinoma, 25%
Adenoidcystic, 25%
Acinic cell, 10%
Epidermoid, 5% to 10%
Other, 1% to 5%
C. Natural history
1. Risk factors
a. Previous exposure to ionizing radiations
b. Skin cancer of face
2. Clinical presentations
a. Mass, often painless, in salivary gland
b. Neurologic changes with involvement of facial nerve
c. Younger women, older men
3. Lymphatic drainage
a. Parotid gland to preauricular, jugulodigastric, intraglandular nodes
b. Submaxillary gland to submental, jugulodigastric, intraglandular nodes
4. Prognostic factors
a. Tumor type and grade
b. Tumor site and extent
c. Tumor involvement of surgical margins; attempts to spare facial nerve resulting in inadequate resection
d. Regional node metastases
D. Diagnosis. Differentiate from inflammatory changes with tenderness of mass and warmth of overlying skin plus hematologic changes.
1. Mass in salivary gland, usually painless, often fixed
2. Paresis and/or numbness related to involvement of facial nerve
3. Biopsy
4. CT or MRI of primary site and neck
E. TNM staging. The AJCC staging system includes malignant tumors of the parotid, submandibular, and sublingual glands. Clinical staging includes inspection, palpation, neurologic evaluation of cranial nerves, MRI, and CT. Pathologic staging includes clinical staging data, plus findings in the resected tissue and the surgeon’s observations.
TNM staging and stage groups are shown in Table 7.1. Primary tumor T1–T4 classification for cancers of major salivary glands is as follows:
T1 Tumor ≤2.0 cm without extraparenchymal extension
T2 Tumor >2.0 but not >4.0 cm in greatest dimension without extraparenchymal extension
T3 Tumor >4.0 cm and/or with extraparenchymal extension
T4a Moderately advanced local disease: tumor invades skin, mandible, ear canal, and/or facial nerve
T4b Very advanced local disease:tumor invades base of skull and/or pterygoid plates, and/or encases carotid artery
F. Management of primary tumor
1. Surgery is the treatment of choice, if the tumor is resectable. Minimal surgery for parotid tumors is superficial parotidectomy with preservation of the facial nerve. Unwelcome sequelae, if extensive surgery is performed, include facial nerve palsy and auriculotemporal syndrome with gustatory sweating.
2. RT has a secondary role as postoperative adjuvant therapy when the histology is poorly differentiated, when significant perineural invasion is seen, or the surgical margins are not tumor-free. RT is also used when the tumor has recurred. Primary irradiation for medically inoperable patients has had some success. Salivary gland tumors seem responsive to fast neutron teletherapy.
3. Local tumor control rates
a. Surgery alone
tages I–II: 95% to 100%
Stages III–IV: 40% to 50%
Low grade: 90%
High grade: 40%
b. Surgery plus RT
Stages I–II: 95% to 100%
Stages III–IV: 75%
Low grade: 90%
High grade: 80%
c. RT for nonresectable disease
Using photons 25%
Using fast neutrons 65%
G. Management of the neck
1. Small, low-grade tumors. Surgery when adenopathy is present
2. Extensive, poorly differentiated tumors. Surgery plus postoperative RT
X. CANCERS OF UNKNOWN PRIMARY (CUP) TO NECK LYMPH NODES
A. Definition. CUP are metastatic solid tumors (hematopoietic malignancies and lymphomas are excluded) for which the site of origin is not identified despite history, physical examination, imaging, routine blood and urine studies, and thorough histologic evaluation.
B. Pathology. Metastases are located in the upper jugular chain in most patients. The histologic type of metastasis to neck nodes varies in incidence according to anatomic location (Table 7.3); the probability for squamous carcinoma rises the higher the node is on the chain. Involved nodes are single in 75% of patients, multiple but ipsilateral in 15%, and bilateral in 10%. Multiplicity is often associated with adenocarcinoma or metastases from the nasopharynx or infraclavicular sites.
Table 7.3 Histology of Neck Node Metastases from Unknown Primary Site
aMalignant melanoma accounts for most cases with other histologies.
C. Natural history. CUP accounts for 3% to 9% of head and neck cancers. The occurrence of CUP to cervical lymph nodes is six times higher in men than in women. Patients are usually heavy smokers and heavy drinkers who have noted the mass for several months. Despite the absence of a detected primary site, both long-term survival and cures are observed in a significant percentage of patients.
1. Upper cervical nodes. The primary site is the upper respiratory passages for most squamous tumors that present as CUP in the upper half of the neck. About 35% of these patients can potentially be cured. With CT or MRI scanning and skillful endoscopic evaluation, a primary site can be determined in at least 30% of cases.
Carcinomas of the nasopharynx, hypopharynx, base of the tongue, and tonsil present with cervical node metastasis as the first manifestation of disease in 30% to 50% of cases. These sites or the larynx harbor the primary tumor 95% of the time when the primary site is ultimately found after initially manifesting as CUP to cervical nodes.
2. Lower cervical nodes. About 65% of metastases to the low cervical nodes originate in sites below the clavicle, most commonly in the lung. Thus, this presentation is usually associated with a poor prognosis.
3. Supraclavicular nodes. Involvement of this group of lymph nodes with malignancy nearly always indicates disease that is far advanced. The primary site is usually the lung, breast, or gastrointestinal tract. The expected survival time is <6 months.
4. Prognostic factors. Prognosis is predominantly affected by the N stage of neck disease, by the location in the neck (see above), by the histopathology, and by whether the primary site is ever found (the prognosis is much better if the primary tumor never becomes manifest).
D. Diagnosis. Excisional biopsy of cervical nodes should not be performed because it distorts surgical planes and may result in poor outcomes if it is proved to be a squamous cell carcinoma originating in an occult site in the head and neck. Supraclavicular lymphadenopathy, on the other hand, rarely represents curable disease; these nodes may be excised directly for histologic examination. The recommended sequence of evaluation of cases of potentially cancerous cervical nodes is as follows:
1. Initial evaluation. Carefully inspect and palpate all accessible areas of the mouth and nose. Then evaluate the upper airways, especially the nasopharynx, with mirrors or Hopkin laryngoscope.
2. Imaging. Obtain a CT or MRI scan of the neck and paranasal sinuses to search for a primary tumor. Positron emission tomography with CT (PET/CT) before obtaining biopsies is often useful if the CT or MRI fails to identify the primary site.
3. Fine-needle aspiration (FNA) is performed if these efforts fail to demonstrate any hint of a primary cancer. The results of cytologic evaluation direct further evaluation, as follows:
a. Squamous cell or undifferentiated carcinoma. Perform panendoscopy and manage the patient for a primary head and neck cancer.
b. Indeterminate or equivocal histology. Excise the node, and perform immunoperoxidase stains and other special studies on the tissue as necessary.
c. Adenocarcinoma. Manage as for CUP to viscera (see Chapter 20). The outlook is nearly hopeless unless originating in a major salivary gland (which is rare).
d. Melanoma. Manage as discussed in Section V.A of Chapter 20.
e. Lymphoma. Manage accordingly (see Chapter 21).
4. Panendoscopy (nasopharyngoscopy, laryngoscopy with tracheoscopy, bronchoscopy, and esophagoscopy) is performed under general anesthesia. All suspected lesions and random areas of apparently normal tissue at the base of tongue, pyriform sinus, and nasopharynx are subjected to biopsy in search of a primary source. Ipsilateral tonsillectomy has a better yield than tonsillar fossa biopsy and is often performed as well. If a primary tumor is found, treatment is planned with consideration of the primary site and neck metastasis.
5. Biopsy of the suspect node should be done only when
a. Thorough physical examination fails to reveal a primary tumor
b. CT or MRI examination does not disclose a primary tumor
c. FNA cytology fails to reveal the diagnosis
d. Panendoscopy fails to reveal a primary site
e. Lymphoma is suspected (excluded in the definition of CUP)
E. Treatment alternatives. Treatment should follow the guidelines for locally advanced SCCHN. Treatment must be comprehensive at the outset because salvage therapy has a low yield.
1. Comprehensive RT (encompassing the nasopharynx, oropharynx, hypopharynx, and both sides of the neck) achieves a high rate of local control in the neck. In theory, RT fields should encompass the undiscovered primary tumor. Less extensive RT, however, has been shown to be associated with the same good results and less morbidity.
2. Surgery. The use of surgical treatment alone should be discouraged in these patients because primary sites in the head and neck become manifest in approximately 40% of patients treated with ND alone. Furthermore, 20% to 50% of patients treated with surgery alone develop contralateral neck disease or subsequently manifest a primary tumor site. The incidences of subsequent manifestation of a primary site or development of contralateral neck disease are both much less after RT than after ND.
3. Chemotherapy. Randomized trials have demonstrated the superiority of cisplatin-based CCRT in patients with known primary site SCCHN at high risk for local recurrence. The application of CCRT to CUP involving cervical lymph nodes in appropriately selected patients appears to be a logical extension of those findings. In general, subjects with SCCHN CUP in the neck do better when the primary site is not found. It is generally agreed that N1 tumors should be treated without chemotherapy. Several single institutional studies have shown impressive survival rates with CCRT for N2–3 disease. Most randomized studies do not include CUP, however.
F. Recommended treatment. Many centers use RT for all cases and CCRT for patients at particularly high risk for local recurrence.
1. Stage N1 involving upper or middle neck node. Treat patients with RT alone. Alternatively, perform ND (particularly if the metastasis is <3 cm in diameter); if the specimen reveals other involved nodes (stage N2b) or extracapsular invasion, administer postoperative RT or CCRT.
2. Stage N2 involving upper or middle neck nodes. Use RT or CCRT followed by ND or after ND.
3. Stage N3 (massive nodes). Use RT alone or CCRT in medically suitable patients. ND should be performed either before or after RT or CCRT.
4. Squamous cell carcinoma of lower cervical or supraclavicular nodes or adenocarcinomas. Administer RT alone (survival rates are poor no matter what is done; the goal of treatment is control of local disease).
G. Results of treatment. In patients with CUP survival outcomes are influenced by clinical stage at time of diagnosis and the presence of extracapsular extension. No significant 5-year survival difference has been seen between patients treated with chemotherapy with radiation alone when compared to patients who also received surgical treatment.
1. Patients with upper cervical lymph node metastasis. The 5-year survival rate for all patients is 30% if the primary tumor is eventually found and 60% if it is never found.
a. Stage N1 or N2a. The 5- and 10-year survival rates are both 70% to 80%. At 10 years after treatment, the risk of finding a primary site is about 30%, which is same as the odds of developing a second cancer after successful treatment.
b. Stage N2b. The reported survival rates are variable.
c. Stage N3. The 5-year survival is about 20%.
2. Patients with low cervical or supraclavicular lymph node metastasis. The 5-year survival rate is 5% (median survival time is 7 months).
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