Initial Head and Neck Examination

An initial examination of the head and neck should be performed with the patient sitting upright in a chair. A standard and complete head and neck examination should then be conducted, including inspection of the head and neck skin and scalp. Cranial nerves II through XII should be assessed. Ear examination with otoscopy should be performed. Nasal examination may be performed with anterior rhinoscopy or nasal endoscopy as indicated. Examination of the oral cavity is performed with a headlight to allow bimanual examination of the lips, buccal mucosa, gingiva, floor of the mouth, and oral tongue. Palpation of the oral tongue and the base of the tongue is crucial for a thorough evaluation. The tongue base and larynx are examined, using a mirror or, preferably, flexible fiberoptic laryngoscopy. While viewing the larynx fiberoptically, the physician should ask the patient to perform several maneuvers: vocalization to allow assessment of vocal cord motion; tongue protrusion to aid in viewing the vallecula; and filling the cheeks with air to help visualize the pyriform sinuses. After the subglottis is evaluated, the laryngoscope can be removed and the examination completed with palpation of the parotid glands, thyroid, and cervical nodes. The size, mobility, and consistency of any mass should be carefully noted.

Staging Investigations

Radiography is a necessary component of the evaluation. It is standard practice to order a computed tomography (CT) scan of the head and neck, preferably with contrast, for any patient with suspected cancer. Not only does this examination help to evaluate the size and location of the primary tumor, but it also helps assess for any possible lymph node metastasis. A magnetic resonance imaging (MRI) scan can provide useful additional information in certain cases, such as nasopharyngeal lesions, skull base lesions, soft tissue tumors, and for the assessment of parapharyngeal space lesions. Routine preoperative laboratory studies may be obtained if surgery is being considered, as well as medical consultations as indicated.

If a suspicious mucosal lesion is anatomically accessible, a biopsy may be undertaken in the clinic after administration of a local anesthetic. Generally, biopsies of oral cavity lesions and selected oropharyngeal lesions are performed in an outpatient setting. Biopsies of selected lesions of the tongue base, larynx, and hypopharynx may also be performed in the clinic with flexible laryngoscopes with biopsy ports, although most lesions require direct laryngoscopy and biopsy with the patient anesthetized. During this procedure, flexible esophagoscopy can be considered to rule out tumor involvement of the cervical esophagus. If lymphadenopathy is identified by palpation, the abnormal node may be assessed by means of fine-needle aspiration (FNA). Radiographically suspicious nodes that are not easily palpable can be assessed by ultrasound-guided or CT-guided FNA. An open biopsy of a neck node should be considered only if findings of FNA are inconclusive.

Currently the American Joint Committee on Cancer (AJCC) staging system, which uses a unidimensional tumor size and local anatomic invasion (T category), nodal involvement (N category), and presence of metastatic disease (M category), is the most widely accepted and applied prognostic system relating to cancer.6,7 Generally, T1, T2, and T3 represent increasing tumor size, whereas T4 is defined by invasion of a surrounding structure (i.e., skin, nerve, vessel, and cartilage). The node (N) category is classified largely by size and location (ipsilateral vs. contralateral) of involved lymph nodes. The absence or presence of distant metastases is defined as M0 if absent or M1 if present. The T, N, and M categories are combined into overall AJCC stages that are presented in Table 68-1. Because the natural history of HNC varies somewhat according to specific anatomic location of the primary disease and because stages III and IV include a large number of different T and N stages, it is customary to refer to specific head and neck cancers by their individual T, N, and M stage and the primary site.

Follow-up Program

After completion of initial treatment, patients are carefully assessed for response to treatment. For advanced-stage cancers treated with chemoradiation therapy (CRT), CT, positron emission tomography (PET), and/or MRI scans are obtained to assess radiographic disease response approximately 12 weeks after completion of treatment. Thereafter patients are seen at gradually increasing intervals for surveillance examinations. Chest radiographs may be obtained intermittently as indicated for surveillance for metastatic disease or secondary primary malignancies, particularly for patients with a history of smoking. Thyroid-stimulating hormone levels should be checked every 12 months because 20% to 25% of patients who have had neck irradiation experience hypothyroidism, necessitating thyroid hormone supplementation.⁸ After 5 years, patients may be examined yearly.

Defining Treatment Algorithms—Primary Site

The single-modality principle for treatment of early-stage disease attempts to minimize toxicity and emphasizes the importance of patient and tumor selection. When postoperative RT (PORT) appears likely, definitive RT may be more appropriate, particularly for small-volume disease, because it is unclear that combined modality therapy is superior to RT alone. This consideration is particularly relevant when initial definitive en bloc resection may, in combination with PORT, further complicate treatment toxicity and organ function. Not uncommonly, these issues arise with more extensive early-stage HNSCC or in cases in which the anatomic location limits achieving adequate surgical margins. For unresectable locally advanced disease, conventionally fractionated RT has been traditionally recommended. Suboptimal local-regional disease control in the absence of surgical options has forced investigation into various modalities of treatment intensification, including neoadjuvant chemotherapy, concurrent CRT, and altered fractionated RT.9,10

Although the AJCC staging system is the most widely accepted and applied prognostic system in persons with cancer, much attention has been given to its inability to identify patients with HNC who are at high risk of treatment failure.⁷ As such, various radiographic biomarkers have been studied to help improve our ability to prognosticate outcomes for individual patients.

During the past decade, interest has expanded in the use of PET-CT, specifically given its ability to be an accurate and sensitive imaging modality for the pre- and posttreatment evaluation of patients with HNC compared with clinical examination and CT alone.11,12 Controversy has plagued studies evaluating the prognostic and predictive utility of the standardized uptake value, essentially the metabolic tumor activity. The success of metabolic-based radiographic biomarkers rests on the ability to standardize protocols allowing interinstitutional comparisons.

Similarly, some volumetric indices have been explored as potential prognostic and predictive indices. Multiple studies have demonstrated that the gross tumor volume correlates with local-regional control and survival in patients with HNSCC who are undergoing surgery,¹³ RT,^16–16 or CRT treatments in various HNC sites.^17–21 Further incorporation of metabolic volume metrics in defining tumor volume, such as the metabolic tumor volume, has defined yet another prognostic radiologic biomarker.^7,22,23 Unfortunately, no volumetric cut points have been prospectively validated.

Defining Treatment Algorithms—Management of the Neck

Traditionally, the management of the primary tumor site dictated the treatment modality for the neck as a strategy to facilitate efficient management of HNSCC. Treatment decisions for the neck have adopted a similar therapeutic paradigm of risk stratification to optimize the therapeutic ratio, but the algorithm becomes more complex as a result of the primary treatment considerations. Conceptually, the issue of functional organ preservation also may be extended to the neck, because neck dissection may result in cosmetic changes and compromised neck and shoulder function. Similarly, RT-induced edema and fibrosis may compromise the goal of functional neck preservation and may be exacerbated by a neck dissection.

Typically, combined-modality strategies are used for the treatment of neck disease. In a neck with negative clinical findings, when surgical resection has been elected for the primary site management, elective neck dissection may be omitted for most subsites if preoperative evaluation determines a high risk of requiring PORT and the risk of occult nodal metastasis is sufficiently high to warrant elective management. When RT has been selected for management of the primary site, neck dissection in a neck with negative clinical findings is not indicated. In fact, pre-RT neck dissection may alter the lymphatic flow of the neck, necessitating larger volumes of the neck to be irradiated. Pre-RT neck dissection also may contribute to delays in the delivery of RT, which have been reported in a retrospective analysis to contribute to an adverse overall survival when compared with post-RT neck dissection.24,25

When conventionally fractionated RT alone has been used for locally advanced HNSCC, suboptimal regional control rates coupled with the morbidity and the limited success of subsequent salvage neck dissection have prompted the incorporation and general acceptance of a planned neck dissection. This approach, in the presence of residual adenopathy after RT, also has been selectively applied to patients with adverse risk factors such as large nodal size (typically 3 cm or greater). This risk stratification is based on RT series demonstrating an inverse relationship between nodal size and control rate.26,27 In a study of RT alone for treatment of HNSCC in 1251 patients, Dubray and colleagues²⁷ noted 3-year neck control rates, by maximum nodal size, of 77% for 0.5 cm, 67% for 2 cm, 60% for 4 cm, 52% for 6 cm, 37% for 8 cm, and 7% for 10 cm. Multivariate analysis revealed that regional relapses independently increased with increased nodal size (P = .0001), decreased radiation dose (P = .0001), T4 primary disease (P = .0001), node fixation (P = .02), bilateral neck disease (P = .03), and geographic miss (P = .0001).

Controversy continues, however, regarding the benefit of a planned neck dissection in the setting of a complete clinical response in the neck, particularly in large pretreatment lymph nodes, after completion of RT.30–30 Treatment with conventionally fractionated RT has demonstrated that the prognosis of large neck nodes with a complete response is associated with a prognosis comparable with that of smaller nodal metastases, and that the risk of relapse is low.^26,31 This finding suggests that perhaps the subgroup of patients with a complete response in the neck may have more radiosensitive disease and may not require a neck dissection. A neck dissection continues to be favored for persons with advanced neck disease (especially stage N3), because the likelihood of achieving a complete response with RT alone is limited. In addition, assessment of disease response by PET/CT allows a more objective evaluation of patients who would likely benefit most from a neck dissection.

Second Primary Tumors

Management of patients with HNSCC is further complicated by the risk for the development of second primary carcinomas and relapses within an aerodigestive tract that may have been extensively exposed to prior treatment. An irradiated aerodigestive tract not only limits reirradiation but also may preclude an effective surgical salvage, because concerns of residual microscopic disease often exist in cases that would otherwise warrant use of PORT. When a second primary or relapse occurs within a previously irradiated field, surgical resection should be the primary treatment option.³² Experiences with various repeat external beam radiotherapy (EBRT) strategies, including the integration of chemotherapy, have unfortunately demonstrated limited success, often at the risk of significant toxicities.^32,33 The exception appears to be nasopharyngeal carcinomas (NPCs) that are more radiosensitive. Even then, significant late complications may arise but may need to be considered in view of the limited surgical options.

Neck Dissection

A variety of different types of neck dissections may be performed (Fig. 68-1). The radical neck dissection is a procedure wherein the lymph nodes from all five levels of the neck, the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve are all removed en bloc. This procedure is indicated in the setting of high-volume neck metastases involving these nonlymphatic structures.

A modified radical neck dissection removes lymph nodes from all five levels of the neck but spares one or more of the nonlymphatic structures. Three types of modified radical neck dissection are type I (which spares one structure, most commonly the spinal accessory nerve), type II (which spares two structures, most commonly the spinal accessory nerve and the internal jugular vein), and type III (which spares all three structures—the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle). A type III dissection also is termed a functional or Bocca neck dissection.³⁴ Of these three structures, removal of the accessory nerve is generally considered to result in the most clinically significant functional deficit from shoulder dysfunction.

Selective neck dissections involve the resection of fewer than all five levels of lymph nodes, usually involving three or four levels according to the site of the primary cancer. These neck dissections are commonly performed in the setting of necks classified as N0, but they may be performed in selected cases of N⁺ nodal disease.37–37

Postoperative Radiotherapy

For more advanced primary lesions (typically defined as stage T3 and T4 disease), increased treatment-related toxicities generally have been accepted because of their inferior local control rates. Accordingly, a combined-modality approach typically has been used. Traditionally, this approach has included surgery and RT with either preoperative or postoperative conventionally fractionated RT. A postoperative protocol generally has been favored because the RT can be delayed until more accurate delineation of the tumor extent of disease and histopathological stratification of patients requiring PORT.⁴⁹

PORT has been demonstrated to provide superior outcomes in a subset of patients with HNSCC compared with preoperative RT. The indications for PORT are based on factors associated with an increased risk of local-regional recurrence after surgery, including advanced tumor stage (T3/T4), presence of a positive margin, extracapsular spread outside lymph nodes, lymphovascular invasion, perineural invasion, presence of a lymph node greater than 3 cm, and multiple positive lymph nodes. When evaluated in a randomized trial in 277 patients with supraglottic larynx and hypopharynx carcinomas (Radiation Therapy Oncology Group [RTOG] trial 73–03), PORT demonstrated superior local-regional control rates compared with preoperative RT, although the results were confounded by use of a higher dose delivered in the postoperative setting.⁵⁰

Poor risk factors such as the presence of extracapsular extension or positive margins require the addition of chemotherapy to PORT. In a study of 334 patients with tumors possessing high-risk pathological features and who underwent surgery with curative intent, EORTC trial 22931, patients were randomly assigned to postoperative RT alone (66 Gy) versus PORT with concurrent cis-diamminedichloroplatinum (CDDP; cisplatin) (with a dose of 100 mg/m² on days 1, 22, and 43 of the RT regimen).⁵¹ Postoperative concurrent CRT (POCRT) significantly improved progression-free survival (HR 0.75; 95% CI 0.56-0.99) and overall survival (HR 0.70; 95% CI 0.52-0.95) and reduced the cumulative incidence of local-regional recurrence in patients receiving POCRT compared with RT alone. Similarly, RTOG 95-01, which randomized 459 patients with high-risk pathological features to receive PORT alone (60 to 66 Gy in 30 to 33 fractions) or RT plus concurrent cisplatin (100 mg/m² on days 1, 22, and 43), reported that POCRT yielded significantly improved rates of local-regional control (HR 0.61; 95% CI 0.41 to 0.91) and disease-free survival (HR 0.78; 95% CI 0.61 to 0.99). Not surprisingly, CRT resulted in greater grade 3 or greater acute toxicity compared with RT alone (77% vs. 34%, P < .001). Pooled analysis of these two trials suggested that PORT with cisplatin should be considered for patients with either a positive margin or extracapsular extension.⁵²

Recent randomized trials have permitted the identification of prognostic factors adversely influencing the outcome, particularly in high-risk patients.53,54 Of greater significance, it is now clear that the time from surgery to the start of PORT and the overall treatment time of PORT are important determinants of local-regional control.⁵⁵

Brachytherapy

Although brachytherapy previously had a significant role in the management of HNSCCs, its current role in the initial management of HNSCC has decreased in the modern era. With the advent of IMRT and the routine use of concurrent chemotherapy, brachytherapy has become less used in the upfront setting, although this is not true in the recurrent setting. It is important to note that studies have demonstrated good outcomes with brachytherapy implants in the definitive setting for several tumor sites, including the tonsil and soft palate,56–61 oral tongue,^62–65 base of tongue,^66–73 and lip.^74,75

Epidemiology

Nasopharyngeal cancer exhibits regional bias with age-adjusted incidence rates (per 100,000 people per year) among men ranging from 0.6 in the United States and Japan, 5.4 in Algeria, 11.0 in Singapore, 17.2 among Eskimos, to 26.9 in Hong Kong and Guangdong province in Southern China.108–108 This discriminative geographic distribution is likely of a multifactorial etiology related to geographic virus infectivity rates, genetic associations, and regional environmental causes. The high consumption of salted fish in Southern China has been implicated, largely as a result of high concentrations of dimethylnitrosamine, a suspected human carcinogen.^109–112 Genome-wide association studies have identified HLA A2, B46, and B17 as associated with an increased risk of developing nasopharyngeal carcinoma.^113–116 Cigarette smoke, alcohol consumption, and exposure to formaldehyde have also been associated with increased risk of NPC.^117,118 Epstein-Barr virus (EBV), one of the seven classified oncoviruses discussed in Chapter 11, has been associated with NPC, specifically the nonkeratinizing type, irrespective of ethnic or geographic origin.^119,120 Increased immunoglobulin (Ig)-A antibodies to EBV have been reported to appear months to years before the clinical onset of NPC and can be used to define populations at high risk of EBV-associated epithelial cancer.¹²¹

Histology/Pathology

NPC constitutes 80% to 95% of nasopharyngeal cancers, with the remaining 5% to 20% consisting of lymphoma (approximately 5%) and less commonly adenocarcinoma, sarcoma, plasmacytoma, and melanoma. The 2005 World Health Organization pathological classification includes three classifications: keratinizing, nonkeratinizing (differentiated or undifferentiated), and basaloid SCC (Fig. 68-9).¹²² Keratinizing and nonkeratinizing SCC in the nasopharynx is morphologically similar to lesions found in the larynx and oral cavity. The nonkeratinizing forms are often EBV-associated and may also take the appearance of transitional epithelium—hence the designation of transitional type. Basaloid SCC is a rare and highly aggressive variant characterized by cells infiltrating in small to large nests with prominent central comedo-type necrosis. At the edges of the nests, the tumor cells form an organized palisade. In addition, variable areas of the tumor show malignant squamous cell morphology with keratinization. Cytologically, the tumor cells show marked nuclear pleomorphism with single cell necrosis and high mitotic rates. Histologic differences between these three classifications are not distinct, and many NPCs are histologic hybrids.

Diagnostic/Staging Workup

Pretreatment diagnostic evaluations include a comprehensive medical history, complete physical examination with added focus on palpation of cervical and supraclavicular neck nodes, cranial nerve testing, abdominal palpation for hepatomegaly and/or splenomegaly, and a spine/bone examination to assess for tenderness, fiberoptic endoscopy, and otologic assessment with baseline audiologic testing (recommended). Laboratory tests should include a complete blood cell count, basic metabolic panel, liver function tests, urinalysis, and EBV-specific serologic tests including antibody titers (IgA, IgM, and IgG), antiviral capsule antigen titers, and serum EBV-DNA levels. Radiographic studies are required to assess local-regional disease with preference for MRI, but CT remains an acceptable alternative.125–125 A chest radiograph should be obtained for all patients. Further radiographic studies to define distant metastases are required in patients with local-regional advanced disease (e.g., stage N3 disease) with initial preference given to PET and chest radiography, but further recommendations include CT of the chest and abdomen in patients with abnormal liver function tests or clinical suspicion of lung or liver metastases and a bone scan in patients with advanced local-regional disease, elevated alkaline phosphatase, and/or symptoms suggestive of bone metastases.

Prognostic Factors

Current staging of NPC is based on the 2010 AJCC staging system (Table 68-5). Updates to the 2010 publication included some changes in the staging of NPC worth noting. Former stage T2a lesions were downstaged to T1 lesions, and hence former stage IIA is now stage I, in an effort to separate tumors confined to the nasopharynx or with extension into the oropharynx or nasal cavity without parapharyngeal involvement versus those with parapharyngeal involvement, which are now classified as stage T2 (previously stage T2b). Hence the previous stage IIB is now stage II. The nodal classification was slightly updated as retropharyngeal lymph nodes, regardless of laterality, are now considered stage N1 lesions. These changes are important to consider when reviewing literature prior to and after the implementation of the seventh edition of the AJCC. Advanced T category is associated with worse local control, whereas advanced N category is associated with an increased risk of distant metastasis and inferior survival. Metastatic disease is associated with a poor prognosis, and treatment options generally focus on palliation. A worse prognosis is associated with cranial nerve involvement, bone erosion, and lower lymph node level disease.^126–129 The presence of EGFR expression is associated with inferior rates of survival.^132–132

Table 68-5

American Joint Committee on Cancer Nasopharyngeal Carcinoma Staging

Stage	Staging Criteria
T CATEGORY
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor confined to the nasopharynx, or tumor extends to nasal cavity* and/or oropharynx† without parapharyngeal extension‡
T2	Tumor with parapharyngeal extension‡
T3	Tumor involves bony structures and/or paranasal sinuses
T4	Tumor with intracranial extension, involvement of cranial nerves, hypopharynx, orbit, or infratemporal fossa/masticator space§
N CATEGORY
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Unilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa, and/or unilateral or bilateral retropharyngeal lymph node(s), ≤6 cm in greatest dimension
N2	Bilateral metastasis in cervical lymph node(s), ≤6 cm in greatest dimension, above the supraclavicular fossa
N3	Metastasis in lymph node(s) >6 cm and/or to supraclavicular fossa
	N3a. >6 cm in dimension
	N3b. Extension to the supraclavicular fossa
M CATEGORY
M0	No distant metastasis
M1	Distant metastasis

^*Nasal cavity: anterior extension beyond the posterior margins of the choanal orifices.

^†Oropharynx: inferior extension beyond the level of the free border of the soft palate. The junction at C1/C2 level is recommended as a more consistent radiologic landmark (37).

^‡Parapharyngeal extension: posterolateral infiltration beyond the pharyngobasilar fascia.

^§Masticator space and infratemporal fossa: Extension beyond the anterior surface of the lateral pterygoid muscle, or lateral extension beyond the posterolateral wall of the maxillary antrum, and the pterygomaxillary fissure.

Supraclavicular fossa: Triangular region defined by the superior margin of the sternal end of the clavicle, the superior margin of the lateral end of the clavicle, and the point where the neck meets the shoulder.

From Edge SB, Byrd DR, Compton CC, et al., editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010, and Sobin L. International Union Against Cancer: TNM classification of malignant tumours. 7th ed. Oxford: Wiley-Blackwell; 2009.

EBV, which is strongly associated with development of NPC, has been demonstrated to be an important biomarker because the presence of serum EBV has a high sensitivity (96%) and specificity (93%) for detecting NPC. Circulating EBV-DNA levels have been demonstrated to correlate with tumor burden, and pretreatment EBV-DNA levels were demonstrated to be an independent prognostic variable in NPC, allowing the dichotomization into high-risk (≥4000 copies/mL) and low-risk (<4000 copies/mL) cohorts.133,134 More recently, two studies have demonstrated that the clearance rate of plasma EBV-DNA during the first month of salvage chemotherapy may predict tumor response and overall survival in patients with metastatic/recurrent NPC; an undetectable level after the first cycle indicated significantly a better rate of survival.^135,136

Treatment Strategy Test

Because of the anatomic location of the nasopharynx, surgical resection typically has not been recommended as a result of the inherent surgical complication rates in this area, including the inability to achieve tumor-free margins. Accordingly, RT with or without concurrent chemotherapy is the treatment of choice. For early-stage disease, RT alone may be used with excellent results, with 3- to 4-year overall survival rates ranging from 70% to 100% and 65% to 100% for stage I and II disease, respectively.129,137–139

IMRT has replaced conventional RT as the standard of care in the treatment of persons with NPC.39,40 The intensity of the radiation beams can be modulated to deliver a high dose to the tumor with superior target volume coverage while significantly limiting the dose to surrounding normal tissues.^140–145 Currently a dose-painting approach is being used in some modern IMRT plans, allowing different fraction doses to be simultaneously delivered to tumor volumes and elective nodal regions in a single course of RT.

Prophylactic neck radiation is usually recommended in patients with stage N0 disease given the high incidence of occult neck node involvement with a risk of 40% neck relapse if untreated, which is associated with a significantly higher incidence of distant failure (21% versus 6%) despite successful nodal salvage.104,146 With appropriate doses of radiation, that is, 50 to 60 Gy, the probability of relapse is less than 5%. In a patient with positive clinical findings of the neck, doses of 60 Gy or greater are typically recommended, with average regional control rates of 90% (range, 86% to 96%) and 75% (ranges, 71% to 87%) for neck nodes 3 cm or less and greater than 6 cm, respectively.¹⁴⁷

Studies have demonstrated improved local control in patients with NPC who received >70 Gy,¹⁴⁸ but despite this dose-response relationship, local control for T3/T4 tumors remained below 55% when treated with >70 Gy.^148,149 The results of the Intergroup 0099 study (IG0099) have made concurrent CRT followed by adjuvant chemotherapy the standard of care for persons with stage III and IV NPC.¹⁵⁰ The investigators reported on 147 of the registered 193 patients who were randomly assigned to receive radiation alone (1.8 to 2 Gy per fraction to a total dose of 70 Gy) or radiation (as described) with concurrent cisplatin (100 mg/m² on days 1, 22, and 43), followed by three cycles of adjuvant cisplatin (80 mg/m² on day 1) and 5-FU (1000 mg/m²/d on days 1-4) every 4 weeks for three cycles. The trial was closed after an interim analysis demonstrated a significantly improved 3-year progression-free survival (69% vs. 24%; P < .001) and overall survival (78% vs. 47%, P = .001) for the arm that received chemotherapy compared with the arm that received radiation alone.

Although these data were received with much debate, subsequent studies have confirmed the benefit of concurrent cisplatin-based chemotherapy in persons with stage III/IV NPC. Wee and colleagues¹⁵¹ reported on 221 patients with stage III/IV NPC who were randomized to receive either RT alone (70 Gy in 2 Gy/fraction) or CRT, which consisted of a slightly modified version of the IG0099 regimen: cisplatin (25 mg/m² on days 1-4) for three cycles every 3 weeks, followed by adjuvant cisplatin (20 mg/m² on days 1-4) and 5-FU (1000 mg/m²/d on days 1-4) for three cycles. Concurrent CRT reduced the incidence of distant metastasis by 17% at 2 years (P = .003) and had a superior 3-year overall survival rate (85% vs. 65%, P = .006), respectively. Further supportive data came from a metaanalysis reported by Langendijk and colleagues¹⁵² of 10 trials that randomized patients with NPC to conventional RT or CRT. Subgroup analysis confirmed that patients treated with CRT had an overall survival benefit (HR for death of 0.48) and absolute survival benefit of 20% at 5 years.

Less evidence exists for treatment with CRT for persons with stage II NPC, yet given a substantial risk of distant metastasis, CRT is generally recommended. Chen and colleagues¹⁵³ reported a phase 3 trial of 230 patients with T1-2N1M0 or T2N0M0 disease with parapharyngeal space involvement who were randomized to RT alone or RT with concurrent cisplatin (30 mg/m²); they found that patients treated with CRT had improved overall survival (94.5% vs. 85.8%, P = .007), progression-free survival (87.9% vs. 77.8%, P = .017), and distant metastasis-free survival (94.8% vs. 83.9%, P = .007). However, no statistically significant difference was found in the 5-year local-regional relapse-free survival rate (93.0% vs. 91.1%, P = .29). Importantly, multivariate analysis demonstrated that the number of chemotherapy cycles delivered was the only independent factor associated with survival and distant control. These findings are controversial because according to the updated 2010 AJCC staging system, the disease of 13% of these patients was restaged as stage III.

In almost all CRT studies an increased rate of acute toxicities has been reported, with an increase in late-occurring toxicities being reported in many studies as well. Chen and colleagues¹⁵³ reported that the addition of cisplatin to RT was associated with a significant increase in acute grade 3 or 4 leukopenia/neutropenia (12.9% vs. 0%, P < .001), nausea/vomiting (8.6% vs. 0%, P = .001), and mucositis (46% vs. 33%, P = .04) compared with RT alone. In the IG0099 trial only 63% of patients completed all three cycles of concurrent chemotherapy, and only 55% were able to receive all three courses of adjuvant therapy.¹⁵⁰ Multiple studies have demonstrated that prolonged treatment breaks correlated with inferior outcomes, with investigators estimating that local-regional relapses increased 3.3% per day of treatment interruption.^154,155

In an effort to minimize toxicities associated with concurrent CRT, trials have been designed to evaluate lower but more frequent doses of chemotherapy. Chan and colleagues¹⁵⁶ reported a phase 3 randomized trial of concurrent cisplatin weekly (40 mg/m²) with EBRT in 350 patients. Seventy-eight percent of patients in the CRT arm received at least four cycles of cisplatin, and patients treated with CRT had superior 5-year overall survival (70.3% vs. 58.6%), which just reached significance on multivariate analysis (HR 0.71, 95% CI 0.5- 1.0, P = .049). Although its use has been validated by other studies, weekly doses of cisplatin have never been directly compared with high-dose cisplatin.^157,158

Studies to evaluate less toxic chemotherapeutic regimens in an effort to identify gentler regimens without sacrificing treatment efficacy have been undertaken. Cisplatin is dose-limited by ototoxicity, irreversible peripheral neuropathy, nephrotoxicity, myelotoxicity, and intractable nausea. As such, carboplatin, which carries a more favorable toxicity profile, was studied as a substitute for cisplatin, with comparable efficacy, in a noninferiority trial reported by Chitapanarux et al.¹⁵⁹ Two hundred six patients were randomized to either concurrent cisplatin with adjuvant cisplatin/5-FU (with the same dosage used in the IG0099 study) or concurrent weekly carboplatin (100 mg/m² on days 1, 8, 15, 22, 29, and 36) with adjuvant carboplatin (area under the curve 5 on day 1) and 5-FU (1000 mg/m² over 96 hours) every 4 weeks with no significant difference in 3-year rates of disease-free survival (63.4% vs. 60.9%, P = .9613, respectively) or overall survival (77.7% vs. 79.2%, P = .9884). Importantly, the treatment regimen was better tolerated in the carboplatin group, with 70% (the major dose-limiting factor was thrombocytopenia) completing adjuvant treatment compared with 42% of the patients in the cisplatin arm. Hence, although cisplatin-based treatment should be prioritized, patients with locally advanced NPC who are not candidates for cisplatin may be considered for CRT with carboplatin followed by adjuvant carboplatin/5-FU as an acceptable alternative regimen.^159,160 Similarly, a regimen of weekly oxaliplatin (70 mg/m²) was evaluated in a phase 3 trial of 115 patients randomized to CRT versus RT alone and was reported to be well tolerated with good efficacy, but to date no studies have directly compared this regimen to cisplatin-based regimens, and it is not currently recommended.¹⁶¹

Newer targeted therapies are increasingly being investigated in persons with NPC. Ma and colleagues¹⁶² reported a phase 2 clinical trial of 30 patients with stage III/IV disease who were treated with an initial dose of cetuximab (400 mg/m²) 7 to 10 days prior to initiation of weekly cisplatin (30 mg/m²) and weekly cetuximab (250 mg/m²). Overall, these investigators reported a tolerable adverse effect profile and good efficacy when compared with published reports with 2-year overall, local-regional progression-free, distant metastasis-free, and progression-free survival rates of 89.9%, 93.0%, 82.8%, and 86.5%, respectively. Similarly, bevacizumab, a VEGF inhibitor that is overexpressed in approximately 66% of patients with NPC, has been studied in a multiinstitutional phase 2 trial (RTOG 06-15) of 44 patients to evaluate the toxicity and efficacy of bevacizumab when added to the standard CRT CDDP regimen.¹⁶³

Although CRT is considered the standard of care, the additional benefit provided by adjuvant chemotherapy remains under investigation. Chen and colleagues¹⁶⁴ reported a phase 3 randomized trial at seven institutions in China in which concurrent CRT (66 Gy in 2.0- to 2.27-Gy per fraction with 40 mg/m² cisplatin weekly for 7 weeks) was compared with concurrent CRT (as described) and adjuvant chemotherapy (cisplatin/5-FU) in 508 patients with stage III/IV disease. No significant differences were noted in failure-free survival (P = .13), distant failure-free survival (P = .12), or overall survival (P = .32), but data interpretation was limited because 18% of patients randomized to the adjuvant arm did not receive any adjuvant chemotherapy and 49% required dose reduction. Further, this trial was not designed as a noninferiority trial. Given the increasing rates of distant metastases with current treatment regimens, adjuvant chemotherapy remains the standard of care. Currently, the role of circulating EBV-DNA after concurrent CRT is being investigated to select patients who may benefit the most from adjuvant chemotherapy.¹³³

The addition of induction chemotherapy to concurrent CRT is an active area of interest. A pooled analysis of the two largest phase 2 studies to date demonstrated that the addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in 5-year relapse-free survival (50.9% vs. 42.7%, P = .014) and improvement in 5-year disease-specific survival (63.5% vs. 58.1%, P = .029) in persons with advanced stage NPC.¹⁶⁵ The incidence of local-regional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively. However, no improvement in overall survival occurred (61.9% vs. 58.1%, P = .092). Induction chemotherapy in this setting remains investigational, and patients are currently being recruited for several phase 3 trials.

Various strategies have been used in attempts to improve the survival rates, particularly for locally advanced disease. The first strategy is to optimize local-regional control, not only because it is a major pattern of relapse in this group of patients but also for the potential impact on the risk of distant metastases. The second strategy is the integration of various chemotherapy agents with definitive radiotherapy. Because a dose-response relationship exists for local control¹⁶⁶ and the overall treatment time¹⁵⁵ also appears to have an adverse impact on treatment outcome, several institutions have reported their results using altered fractionation for locally advanced NPC with or without concurrent chemotherapy.¹⁶⁷

Despite the improved outcomes resulting from CRT for intermediate stage and locally advanced NPC, a proportion of patients continue to have persistent disease. An important distinction exists between persistent disease (i.e., tumors that do not completely regress after primary treatment) and recurrent disease (i.e., tumors that reemerge after initial complete regression) because the prognoses and therapeutic considerations are different, with better survival and control rates for persistent disease.¹⁶⁸ Early detection of local-regional failure is crucial for a better chance of salvage, and regular follow-up after completion of primary treatment is recommended. Frequently used methods include manual palpation, rigid nasopharyngeal endoscopy and nasopharyngeal biopsies, imaging techniques (e.g., CT, PET, and MRI), and serologic tests (e.g., anti-EBV titers).

Therapeutic options for persistent disease have generally been centered around further irradiation or observation. Studies have demonstrated that further irradiation in early-stage disease that is amendable to intracavitary and interstitial techniques may result in local control rates comparable to those achieved in patients demonstrating a prompt complete response.¹⁶⁹ Hence dose escalation may be adequate in compensating for tumors that demonstrate a low radioresponsiveness. The optimal dose schedule remains to be determined, with both 60 Gy low dose rate and 22.5 to 25 Gy high dose rate schedules having been reported. Stereotactic radiosurgery has been used, with preliminary data suggesting that up to 70% of patients with organ-confined recurrences may achieve local control for up to 2 years.¹⁷⁰ Late-appearing toxicity does not appear to be increased. In light of the poorer local control rates and survival rates in patients who have local recurrences, a brachytherapy implant or stereotactic radiosurgery may be considered in the management of patients demonstrating persistent disease.

Because NPCs are radiosensitive, locally recurrent carcinomas, they may be amenable to reirradiation. The risk of late-appearing complications including soft tissue and brain necrosis and neuropathies is highly dose and volume dependent with reirradiation, and thus the general strategy has been to incorporate conformal RT techniques for the boost component of the reirradiation regimen. As with treatment for persistent disease, this treatment may take the form of either brachytherapy or a stereotactic radiosurgery boost.¹⁷¹ In a series of more than 891 patients undergoing reirradiation, the extent of the recurrence was prognostic. Overall, approximately 30% achieved local disease control when a repeat radiation dose of 60 Gy or greater was delivered.¹⁷² The selection of small EBRT fraction size and the use of a brachytherapy implant were associated with a reduced risk of late-appearing complications. Several other institutional series have reported sustained local control rates of 20% to 60%, with the variability due to the extent of initial disease at presentation and at recurrence and the dose of reirradiation.^169,173,174 In selected series treating only disease confined to the nasopharynx amenable to management by either intracavitary or interstitial implant, sustained local control rates of 50% to 60% may be realized. These series also have demonstrated a significant risk of developing late-appearing radiation-related complications, including soft tissue and bone necrosis, trismus, fistula formation, and neurologic complications such as radiation myelitis and temporal lobe necrosis.

Many of the recent salvage radiation studies have included cisplatin-based chemotherapy for advanced-stage disease.175–178 Using gemcitabine and cisplatin as induction chemotherapy followed by reirradiation with IMRT in 20 patients (95% of whom had stage rT3-4 disease), Chua et al.¹⁷⁶ reported a 1-year local salvage rate of 75%. In a study of 35 patients (66% of whom had stage rT3-4 disease), Poon et al.¹⁷⁵ reported a 1-year event-free survival rate of 42% with concurrent cisplatin and adjuvant cisplatin and 5-FU. Further study regarding the efficacy and safety of adding chemotherapy to reirradiation approaches is needed.

Salvage surgery is occasionally performed for NPC in select patients. In patients with persistent nodal disease, a radical neck dissection is the preferred treatment if no evidence of distant metastases exists, with at least one study reporting a 5-year nodal control rate of 66% and a 5-year disease-free survival rate of 37%.¹⁷⁹

Surgical management of primary site recurrences is difficult given the complex anatomy and space constraints. Although it is controversial, salvage surgery is being performed at certain centers with limited data published as small retrospective studies, which have demonstrated feasibility and success in local control.180,181 Hsu and colleagues¹⁸¹ studied 60 patients who underwent salvage surgery and showed that patients who underwent surgical resection demonstrated slightly improved local control and overall survival compared with patients who underwent high-dose reirradiation for local relapse, with fewer late complications. These investigators favored salvage surgery for rT1-2 and limited rT3 disease because of the lower complication rate. Access to the pharyngeal recess is of critical importance in the surgical management of recurrent NPC, given the high rate of recurrence in this area. Wei and Sham¹⁸² demonstrated an anterolateral approach or maxillary swing approach for localized recurrence in the nasopharynx. In this approach the maxilla is swung laterally as an osteocutaneous anterior check flap, exposing the nasopharynx. Wei et al.¹⁸³ reported on 161 patients who underwent salvage nasopharyngectomy with use of this approach at Queen Mary Hospital (Hong Kong) for recurrent NPC after primary treatment by radical RT. Twelve patients had prior brachytherapy as a salvage procedure. All patients had recurrent stage T1 disease, with 78% of these patients achieving negative tumor resection margins, confirmed by frozen section; the remaining patients had positive microscopic margins at the internal carotid artery or the skull base. All patients recovered from this anterolateral approach and were discharged. Significant surgical morbidities included trismus (60%) and palatal fistula (25%). Postoperative reirradiation is recommended for patients with positive surgical margins and/or advanced disease,^186–186 whereas its potential benefit in patients with negative surgical margins remains to be determined.¹⁸⁷

Treatment-Related Toxicities

Given the anatomic complexity of the nasopharynx with its proximity to critical structures combined with the need for high radiation doses, the risks of acute and late-appearing treatment-related toxicities are significant. The overall complication rate from conventional treatment ranges from 31% to 66%, with severe sequelae including temporal lobe necrosis, hearing loss, xerostomia, neck fibrosis, cranial nerve dysfunction, carotid artery injury/rupture, endocrine dysfunction, soft tissue necrosis, osteonecrosis, and transverse radiation myelitis.101,188,189 As mentioned previously, IMRT is now considered the standard of care for NPC given the improved toxicity profile as exemplified by Lee et al.,¹⁴⁴ who demonstrated that IMRT is superior in the preserving salivary function, a finding subsequently confirmed by others.^190,191 Reirradiation carries a significantly greater risk of the development of treatment-related toxicities and should largely be performed at specialized centers.

Nasal Cavity and Paranasal Sinus Cancer

Malignant tumors of the sinonasal tract are relatively rare, constituting approximately 3% of upper respiratory tract cancers. Accordingly, the scientific literature is limited to multiple small retrospective reports describing the treatment and outcomes of patients with these tumors, which has limited progress in defining the optimal management for these malignancies.

Among the different subsites within the paranasal sinus, SCCs occur most commonly in the maxillary sinus.¹⁹² The second most common location is the nasal cavity, and the remainder originate in the ethmoid sinus, which is also the more frequent location for the histologic variants adenocarcinoma and esthesioneuroblastoma. Cancer rarely arises in the frontal and sphenoid sinuses.¹⁹²

Paranasal sinus malignancies demonstrate a male predominance (4 : 1 male:female), with risk factors including occupational exposures, air pollution, tobacco smoke, and HPV infection. The prognosis for maxillary and ethmoid lesions is based on the 2010 (seventh edition) AJCC staging system (Table 68-6) and, in the case of maxillary sinus malignancies, on their relationship to Ohngren’s line, a theoretical plane that extends from the medial canthus of the eye to the angle of the mandible. Tumors anteromedial to Ohngren’s line are thought to have a considerably better prognosis, whereas tumors posterolateral to the line carrier a worse prognosis. No standard staging system has been developed for frontal or sphenoid sinus tumors.

Most malignancies are advanced at presentation and commonly involve one or more adjacent structures (Fig. 68-10). Orbital invasion often occurs early with cancers of the maxillary and of the ethmoid sinuses, whereas it often is a late event for nasal cavity tumors. Malignancies beginning in the anterolateral infrastructure of the maxilla often erode through the inferolateral wall and extend into the oral cavity, with involvement of the maxillary gingival or the adjacent gingivobuccal sulcus.

The maxillary sinuses have a poor lymphatic supply. The retropharyngeal nodes are the first echelon lymphatic drainage for sinus malignancies, with other commonly involved lymph nodes being the periparotid and level IB nodes. The risk of cervical node metastases is low unless the tumor has progressed to involve mucosal surfaces with abundant lymphatics, such as the oral cavity. Nodal recurrences, which are reported in approximately 3% of patients, are more frequent for SCC, neuroendocrine tumors, and rhabdomyosarcoma of the paranasal sinus.¹⁹³

Oral Cavity

It was estimated that in 2012 approximately 26,740 new cases of pharyngeal carcinoma would be diagnosed, with approximately 5,520 deaths attributable to oral cavity carcinoma.²⁰¹ When grouped together with pharyngeal cancer, cancer of the oral cavity is the sixth most common cancer in the world.²⁰² Signs and symptoms associated with oral cavity tumors include bleeding, dysphagia, dysarthria, and halitosis. In addition, the patient may report ill-fitting dentures that previously fit properly. At presentation, oral cavity tumors generally present with local invasion, tissue destruction, and lymph node metastases, but distant metastatic disease is uncommon.²⁰²

In the Western world, tobacco smoking and alcohol are the two major risk factors for the development of oral cavity SCC. Buccal mucosa cancer has additional risk factors including ultraviolet radiation and use of oral tobacco and betel nut quid.

The oral cavity (Fig. 68-11) is composed of the lip, anterior two thirds of the tongue (oral tongue), floor of mouth, buccal mucosa, gingiva, hard palate, and retromolar trigone. The floor of the mouth is bounded by the lower alveolar ridge anteriorly and laterally and the ventral tongue surface and anterior tonsillar pillar posteriorly. The tongue is divided into an oral component, which lies anterior to the circumvallate papillae, and the base of tongue, which is a part of the oropharynx and lies posterior to the circumvallate papillae. The buccal mucosa overlies the buccinator muscle, is bounded superiorly and inferiorly by the gingiva, and extends posteriorly to the retromolar trigone. The gingiva is the soft tissue overlying the alveolar ridges of the mandible and maxilla. The hard and soft palates form the roof of the mouth. The retromolar trigone mucosa overlies the mandibular ramus and is bounded anteriorly by the buccal mucosa and posteriorly by the anterior tonsillar pillar. The oral cavity has a rich lymphatic supply, and as such, nodal metastases to levels I to III are common. A multidisciplinary approach is critical given the important role that oral cavity structures play, including cosmesis, mastication, deglutition, and speech articulation.

Histology/Pathology

As elsewhere in the head and neck, SCC is the most common histology, accounting for approximately 95% of all malignant tumors in the oral cavity, except in the hard palate, where most tumors originate in the minor salivary glands. Other malignancies involving the oral cavity include malignant mucosal melanoma, lymphoma, and sarcoma. Although SCC can occur anywhere in the oral cavity, the most common locations include the floor of the mouth and tongue. In the earliest recognizable stage, SCC appears as firm, pearly plaques or as irregular, roughened, or verrucous areas of mucosal thickening, which can be mistaken for leukoplakia, a premalignant lesion. Larger lesions seldom are mistaken for leukoplakia and form either exophytic masses (Fig. 68-12, A) or endophytic lesions, often with associated ulceration and heaped-up edges (Fig. 68-12, B). Histologic examination frequently reveals an association with in situ lesions, sometimes with surrounding areas of epithelial dysplasia of varying degrees (Fig. 68-12, C). These tumors range from well-differentiated keratinizing neoplasms to poorly differentiated SCC without keratinization to anaplastic and sometimes sarcomatoid growth patterns (Fig. 68-12, D). Less common patterns include verrucous carcinoma.

The oropharynx anteriorly connects to the oral cavity and joins the nasopharynx with the larynx/hypopharynx. Anteriorly, the oropharynx begins at the base of the tongue and extends posteriorly to the pharyngeal wall (Fig. 68-11). It extends superiorly from the top of the soft palate to its inferior border, the top of the hyoid bone. The four subsites contained within the oropharynx are the base of tongue, the palantine tonsils and tonsillar pillars, the soft palate, and the pharyngeal wall.

The base of tongue begins at the circumvallate papillae and extends inferiorly to the vallecula. Laterally, the base of tongue extends to the glossopalatine sulcus. The palatine tonsils are located on the lateral wall of the oropharynx and are composed of lymphoid tissue in a fibrous capsule. The anterior tonsillar pillar is formed by the palatoglossus muscle, whereas the posterior pillar is formed by the palatopharyngeus muscle. The anterior pillar is posterior to the retromolar trigone. The soft palate serves as the roof of the oropharynx and the floor of the nasopharynx. It connects anteriorly with the hard palate. The pharyngeal wall is composed of the pharyngeal constrictor muscles.

Lymph node drainage from the base of tongue and the palantine tonsils is typically to levels II to IV and the lateral retropharyngeal nodes.36,226,227 The most common site of lymph node metastasis is to the jugulodigastric nodes. Occasionally, levels Ib and V can become involved.²²⁸ Level Ib is at increased risk of involvement with significant invasion of the oral tongue. Midline tumors, such as base of the tongue tumors, are at risk for bilateral lymph node metastasis. Small lateralized tonsillar tumors without midline extension have less risk of contralateral lymphadenopathy.²²⁹

Major and Minor Salivary Gland Cancer

Salivary gland tumors constitute a rare and interesting heterogeneous group of tumors that represent approximately 6% to 8% of head and neck tumors.²⁶¹ The vast majority of salivary gland tumors are benign and develop in the parotid gland.²⁶¹ Tumors in the minor salivary gland are more likely to be malignant (50% to 60%), as are sublingual salivary gland tumors (80% to 90%), in comparison with major salivary gland and parotid tumors (20% to 30%) and submandibular tumors (30% to 40%).

The large majority of patients with major salivary gland cancer present with a painless mass or swelling in the parotid, submandibular, or sublingual gland. Patients with minor salivary gland cancer often present with ulcerations or a submucosal mass on the palate, lips, buccal mucosa, or nasal cavity/maxillary sinus. Similar to nasopharyngeal cancer, minor salivary gland cancer of the nasopharynx usually presents at an advanced stage with invasion of skull base, intracranial extension, or involvement of cranial nerves. The presence of neurologic signs and symptoms is almost always indicative of a malignant rather than benign tumor and is negatively prognostic.²⁶² Additional features suggestive of a malignant parotid tumor include pain, rapid growth, skin involvement, and cervical lymphadenopathy. Negative findings of FNA does not exclude the possibility of malignancy, and pursuing additional biopsies or a parotidectomy may be indicated.

Histology/Pathology

Benign and malignant salivary gland tumors are classified according to the 2005 World Health Organization system.²⁶³

Mucoepidermoid Carcinoma

Mucoepidermoid carcinomas are the most frequent malignancy of the salivary glands. Although they occur most often in the parotid gland, they can also been seen with high frequency in the minor salivary glands. These tumors, as their name implies, are composed of a mixture of squamous cells (epidermoid component) and mucus-secreting cells (mucoid component). A third cell type found within these lesions is the intermediate cell.

Mucoepidermoid carcinomas vary in size and lack a well-defined capsule. Microscopically, the tumor shows a punching or infiltrative border. Tumors vary in appearance from white to gray and frequently contain small to microscopic mucinous cysts (Fig. 68-13, A). Microscopically, the tumor is composed of cells arranged in cords, nests, and sheets with varying amounts of squamous, mucous, and intermediate cells. These tumors can vary from well differentiated to highly aggressive, poorly differentiated histopathology. Various grading schemes to account for these differences cluster tumors into low-, intermediate-, and high-grade categories based on the amount of mucinous cells, solid squamous nests, mitotic rate, necrosis, and pleomorphism.^264,265 These tumor grades also correlate with patient outcome. Low-grade tumors (Fig. 68-13, B) rarely metastasize, often are locally infiltrative, and recur in 10% to 15% of cases and therefore have an excellent 5-year survival rate of greater than 90%. By contrast, high-grade tumors (Fig. 68-13, C), are highly infiltrative, recur in 30% to 40% of cases, and have metastasized in 30% to 40% of cases at presentation, producing a 5-year survival rate of only 50%.^268–268 Grading appears to have less prognostic importance when the submandibular glands are involved. Involvement of this site appears to be associated with an increased risk of distant relapse regardless of grade.

Adenocarcinoma, Not Otherwise Specified

Tumors classified as “adenocarcinoma, not otherwise specified” are now restricted to lesions that do not show histopathological patterns of the other salivary gland tumor types. These tumors can occur in the parotid gland and minor salivary glands and typically present in the sixth to eighth decades of life. At presentation, varying histologic patterns including tubular, papillary (with varying degrees of differentiation from well to poorly differentiated), and adenocarcinoma may be observed. Important in the workup for these patients is to exclude adenocarcinoma that has metastasized from another body site because salivary gland adenocarcinoma can mimic adenocarcinoma from other organ sites.

Adenoid Cystic Carcinomas

Adenoid cystic carcinomas account for some 20% of malignant salivary gland tumors. They are frequently located in the minor salivary glands (in 40% to 50% of cases) and less often in the parotid gland (in 20% to 30% of cases). The most common histologic pattern is the classic cribriform type or “Swiss cheese” pattern, characterized by neoplastic cells that form oval or circular spaces or nests. Within these nests is dark, eosinophilic, hyaline-like basement membrane material. The amount of hyaline material can distort the cell nests and produce a small acinar or cordlike appearance to the tumor nests (Fig. 68-13, D). Perineural invasion is almost invariably observed in these tumors (Fig. 68-13, E), and a diagnosis of adenoid cystic carcinoma without finding perineural invasion should be carefully reconsidered. Adenoid cystic carcinomas are graded into low-, intermediate-, and high-grade tumors based on the amount of solid growth, mitoses, necrosis, and pleomorphism; as with mucoepidermoid carcinoma, the degree of differentiation is correlated with long-term survival.

Acinic Cell Carcinoma

More than 90% of acinic cell carcinomas arise in the parotid gland. These tumors occur between the ages of 50 and 70 years, with men affected more than women. The gross appearance of these tumors varies, but they often are white-tan in color and present as a well-circumscribed but unencapsulated mass. Microscopically, the most common histologic pattern consists of solid sheets of cells with low-grade cytology and granular basophilic cytoplasm similar to the serous acinar cells of a normal salivary gland. Less common variants include a cystic and microcystic pattern in which the tumor cells are arranged at the edges of the cyst and cells with granular basophilic cytoplasm are arranged among cells, with a tombstone appearance and capitation-type section, as well as cells with a bubbly vacuolated appearance. Rare cases of acinic cell carcinoma have been reported to undergo dedifferentiation into high-grade aggressive malignancy; most acinic cell carcinoma tumors, however, behave in a more indolent fashion.

Malignant Mixed Tumor (Carcinoma Ex Pleomorphic Adenoma)

Malignant mixed tumors of the salivary gland are predominantly tumors that started as pleomorphic adenomas in which the epithelial tumor component subsequently underwent malignant transformation. This transformation may be confined to the adenoma, resulting in the noninvasive carcinoma ex pleomorphic adenoma. A majority of carcinomas that arise out of pleomorphic adenomas, however, are infiltrative and aggressive lesions (Fig. 68-13, F and G). The transformation to a malignant phenotype is heralded by a change in the behavior of the patient’s underlying pleomorphic adenoma that is characterized by sudden enlargement of an otherwise stable adenoma. Morphologically, the malignant transformation can take on any malignant epithelial salivary tumor phenotype, the most common being “adenocarcinoma not otherwise specified.” Occasionally, multiple recognizable histologic patterns may be present. These tumors are highly aggressive, with 5-year survival rates as low as 25%. Another form of the malignant mixed tumor is the true carcinosarcoma, which again often arises from a pleomorphic adenoma background. These tumors have both malignant epithelial and malignant stromal elements.

Polymorphous Low-Grade Carcinoma

Polymorphous low-grade adenocarcinoma (PLGA) is a rare low-grade carcinoma of minor salivary glands. These tumors grow as infiltrative masses and are composed of uniformly low-grade tumor cells arranged in a variety of histologic patterns, including tubular, solid, papillary, microcystic, cribriform (with true lumina), pseudoadenoid cystic (without true lumina), fascicular, single file, and cordlike. Perineural invasion is common. In contrast with adenoid cystic carcinoma, PLGA stains positively for epithelial membrane antigen, which may be relied on to distinguish between these two pathologic lesions. Rare cases of PLGA have metastasized, and these cases have been associated with more than focal areas of papillary growth. Rare cases have dedifferentiated into high-grade aggressive carcinomas.

Salivary Duct Carcinoma

Salivary duct carcinomas are rare tumors with a male predilection. They are rapidly growing tumors that can produce pain and nerve palsies. Morphologically, these tumors resemble comedo-type duct carcinoma of the breast and also may grow in a cribriform or papillary pattern. Cytologically, these tumors tend to be high grade, with nuclear pleomorphism, single-cell necrosis, and a high mitotic rate. Clinically, these tumors behave in an aggressive fashion, with poor long-term survival.

Larynx

Knowledge of the anatomy of the larynx is essential to understanding the different treatment modalities used for the varying stages of larynx cancer. The larynx produces speech (phonation) and protects the airway. Treatment-related compromise of either of these functions can dramatically affect patients’ quality of life after treatment for their cancer. In fact, the loss of one’s voice is one of the most dreaded adverse effects in all of oncology.

Anatomically, the larynx is divided into three subsites: the supraglottic, glottic, and subglottic larynx (Fig. 68-14). The supraglottic larynx extends from above the tip of the epiglottis to the laryngeal ventricle and includes the epiglottis, the aryepiglottic folds, the arytenoids, and the false vocal cords. During swallowing, the epiglottis covers the entrance of the larynx and prevents food from entering the trachea. The epiglottis itself is divided into a suprahyoid and infrahyoid portion. The aryepiglottic folds connect the epiglottis to the arytenoids. The arytenoids are paired pyramidal-shaped cartilages that sit on top of the cricoid cartilage and serve as the posterior attachments for the true vocal cords. The false vocal cords lie superior and laterally to the true vocal cords.

The glottic larynx includes the true vocal cords and the anterior and posterior commissure. Inferiorly the glottis extends 1 cm below the apex of the ventricle (surgical definition) or 5 mm below the free edge of the true vocal cord (radiation oncology definition). The vocal cords attach anteriorly to the thyroid cartilage (the anterior commissure) and posteriorly to the arytenoids. The true vocal cords are usually 2 cm long and 3 to 5 mm thick. The majority of malignancies appear on the anterior two thirds of the vocal cord. The true vocal cords are easy to visualize on fiberoptic examination but are more difficult to appreciate on axial CT imaging. Often, a CT slice with both the cricoid cartilage and arytenoids present can be used as a proxy for the location of the true vocal cords. The anterior commissure can lie close to the skin surface and as such for patients receiving RT, administration of a bolus may be necessary to ensure adequate coverage of this area if it is involved with disease.

The subglottic larynx begins below the glottis and extends to the bottom of the cricoid cartilage. The cricoid cartilage is the only complete cartilaginous ring in the larynx and trachea and is usually located at the level of the C6 vertebrae. The largest cartilage in the larynx is the thyroid cartilage, which is superior to the cricoid cartilage.

Early T-stage glottic larynx cancers are very unlikely to drain to lymph nodes because of poor lymphatics in the true vocal cords.²⁷⁵ Locally advanced lesions, including T3 and T4 lesions, have a higher propensity for lymph node spread, because the primary tumor extends outside of the glottis itself. These lesions may spread to levels II to IV, the pretracheal delphian nodes, and to a lesser extent, level V.^36,226 On the other hand, the supraglottic larynx has a rich network of lymphatics, and primary lesions arising here are at risk for bilateral lymph node metastasis, because the supraglottic larynx is a midline structure. Up to 55% of patients present with positive nodes and 16% of patients present with bilateral nodes.