Early HPV-Related Base of Tongue Cancer

33

Early HPV-Related Base of Tongue Cancer AS HISH A. PATEL, ALLEN CHENG, ROM LEIDNER, MARKA R. CRITTENDEN, AMBER L. WATTERS, MEGAN J. HYERS, R. BRYAN BELL

as perineural spread, lymphovascular invasion, and extracapsular extension may affect treatment response and prognosis. Early-stage base of tongue cancers can usually be managed with either surgery or radiotherapy (RT) with excellent oncologic results, particularly in the HPV-positive population. Over the last several decades, RT has served as the dominant approach to treating early-stage OSCC. However, recent advances in minimally invasive surgical techniques, such as transoral robotic 10

Oropharynx (overall) HPV-positive oropharynx HPV-negative oropharynx

Rates per 100,000

A

 pproximately 15,000 new cases of oropharyngeal squamous cell carcinoma (OSCC) are diagnosed annually  in the United States, with 40–50% originating in the base of the tongue.1 As with most head and neck squamous cell carcinomas (HNSCCs), tobacco and alcohol use are significant risk factors for the development of base of tongue cancer. Recently, human papillomaviruses (HPVs), especially HPV type 16, have also been shown to be an important independent risk factor for the development of cancer of the tongue base, with the number of sexual partners being a contributing risk factor. D’Souza demonstrated an increased likelihood of oropharyngeal HPV infection in patients having either 10 oral sex partners (odds ratio, 5.2) or 25 vaginal sex partners (odds ratio, 3.9) during their lifetime.2 Although the overall incidence of HNSCC has declined in the last three decades owing to declining smoking rates among Americans, the incidence of oropharyngeal cancer has risen sharply, particularly in the 40- to 55-year-old male subgroup3 (Fig. 33.1). Surveillance, Epidemiology, and End Results (SEER) data indicate a 13% increase in incidence from 1973 to 2004, with approximately 60% resulting from HPV-­positive infection. Predictive modeling findings from the National Institutes of Health (NIH) project that within the decade the incidence rates of oropharyngeal cancers due to HPV will surpass that of cervical cancer.4 HPV-related OSCC is biologically and clinically distinct from HPV-negative tumors, which respond much less favorably than HPV-positive carcinomas to conventional therapies.5,6 Threeyear overall survival (OS) rates of 40–50% for patients with local regionally advanced HPV-­negative OSCC treated with radiation and chemotherapy have been reported, as opposed to 80% survival for those with HPV-positive carcinomas treated with similar regimens (Fig. 33.2). A meta-analysis by O’Rorke and colleagues that included 42 studies and 4843 patients documented that HPV-positive oral head and neck squamous cell carcinoma (OHNSCC) patients had a 54% OS benefit compared with HPV-negative patients and also showed significantly improved progression-free and disease-free survival.7 Early base of tongue tumors (T1/T2) are limited to the tongue itself and do not involve adjacent structures. In addition to primary tumor classification, other pathologic features such

1

0

0

8

19

9

19

9

1 5–

19

4

00

99

99

1 1–

0

6

2

99

1 8–

2 9–

9

19

00

2 3–

0

20

Calendar years

• Fig. 33.1  Cancers of the oral cavity and pharynx. (From Sturgis EM, Cinciripini PM: Trends in head and neck cancer incidence in relation to smoking prevalence. Cancer, 2007;110[7]:1429–1435.)

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Anatomy of the Base of Tongue

surgery (TORS), have resulted in resurgence of the role of surgery for OSCC. This chapter focuses specifically on the clinical presentation, diagnostic evaluation, and contemporary management of T1/T2 base of tongue squamous cell carcinoma (SCC) from a multidisciplinary perspective.

Overall survival (%)

100

The oropharynx is divided into four clinical subsites: the anterior wall, posterior wall, lateral wall, and superior wall (Fig. 33.3). The anterior wall is further divided into the vallecula and base of tongue. The base of tongue consists of the posterior third or root of the tongue anteriorly bound by the circumvallate papilla, posteriorly by the vallecula, laterally by the glossotonsillar sulci, and inferiorly by the hyoid bone. The base of tongue is rich in lymphatics and contains aggregates of lymphoid tissue—the lingual tonsils—which contribute to the Waldeyer Ring. Unlike the palatine tonsils, the lingual tonsils are unencapsulated and are lined by nonkeratinized squamous mucosa that forms numerous crypts or invaginations on its surface. As previously described, lymphatic drainage of the base of tongue is relatively predictable and includes levels II, III, and IV, with the first echelon of nodes being the upper deep cervical nodes and frequently the jugulodigastric node.8,9 Tumors that encroach on the midline of the base of tongue are more likely to have bilateral lymphatic drainage. Other potential routes of metastatic spread involve the parapharyngeal and retropharyngeal lymph nodes. Cervical lymphadenopathy is commonly the first presenting sign of base of tongue carcinoma.10 The neurovascular anatomy of the base of tongue is derived from the lingual artery and its branches, the lingual veins, and tributaries, and the 5th, 7th, 9th, and 12th cranial nerves.

HPV-positive

75

50 HPV-negative 25 Hazard ratio for death, 0.38 (0.26–0.55); p < 0.001 0 0

Number at risk 206 HPV-positive HPV-negative 117

1 2 3 4 Years since randomization 193 89

179 76

165 65

151 51

5 73 22

• Fig. 33.2  Survival of oropharyngeal cancer patients according to human papillomavirus (HPV) status. In a Kaplan-Meier analysis, patients with HPVpositive cancer had better overall survival and progression-free survival rates than patients with HPV-negative cancer (P < .001 for both end-points, by the log-rank test). The 3-year rates of overall survival were 82.4% (95% confidence interval [CI], 77.2–87.6) in the HPV-positive subgroup and 57.1% (95% CI, 48.1–66.1) in the HPV-negative subgroup, and the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7–79.8) and 43.4% (95% CI, 34.4–52.4), respectively. Patients with HPV-positive tumors had a 58% reduction in the risk of death as compared with patients with HPV-negative tumors (hazard ratio [HR], 0.42; 95% CI, 0.27–0.66) and a 51% reduction in the risk of relapse or death (HR, 0.49; 95% CI, 0.33–0.74). (Adapted from Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35.)

Clinical and Diagnostic Evaluation The clinical presentation, natural history, risk factors, demographics, and outcomes are distinctly different for HPV-related and HPV-unrelated disease. The incidence of HPV-driven oropharyngeal cancer increased 225% between 1988 and 2004, whereas the incidence of HPV-negative oropharyngeal cancer

Turbinate Pharyngeal recess Levator veli palatini m.

Palatopharyngeus m. Palatine tonsil Genioglossus m. Foramen cecum Lingual tonsil

Constrictors

Stylopharyngeus m.

Epiglottis Vallecula Hyoid

Superior horn of thyroid cartilage Superior laryngeal n.

Platysma m.

Epiglottis Piraform recess Cuneiform tubercle Corniculate tubercle

Geniohyoid m.

A

B • Fig. 33.3  Oropharyngeal anatomy. The oropharynx is divided into four clinical subsites: the anterior wall, posterior wall, lateral wall, and superior wall. A, Sagittal view; B, coronal view. The anterior wall is further divided into the vallecula and base of tongue. The base of tongue consists of the posterior third or root of the tongue anteriorly bound by the circumvallate papilla, posteriorly by the vallecula, laterally by the glossotonsillar sulci, and inferiorly by the hyoid bone.

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

decreased by 50%.4 More than 100 HPV subtypes are known to exist, with over 15 having oncogenic potential,11 but 60% of OSCCs are positive for HPV16.12 In the United States, it is estimated that about 40–80% of oropharyngeal cancers are associated with HPV, whereas in Europe the proportion varies from 20% to 90% depending on the prevalence of tobacco use. It is a rising epidemic in the 40- to 55-year-old male population. Unlike conventional base of tongue HPV-negative, keratinizing SCC, HPV-related SCC arises within epithelial-lined crypts of lymphoid tissue—in general, either the palatine or the lingual tonsils (Fig. 33.4). Its pathogenesis is that of an oncovirus. After infection of lingual tonsillar tissue, the virus integrates its genome into the host cell DNA. This in turn upregulates oncoproteins E6 and E7, which are responsible for degrading p53 and retinoblastoma protein (pRb) tumor

suppressor genes.13 The tumors are generally characterized as nonkeratinizing, poorly differentiated, basaloid carcinomas (Fig. 33.4C). Early primary tumors involving the base of tongue are usually asymptomatic. The first presenting sign of T1 or T2 base of tongue cancer is usually painless cervical lymphadenopathy. In some patients, even with small primary tumors, mild symptoms of dysphagia, dysarthria, odynophagia, or globus sensation may be present. Significant dysphagia, weight loss, and hemoptysis may be signs of more advanced disease. These presenting signs, in the absence of heavy cigarette smoking with or without alcohol use, are most characteristic of HPV-associated base of tongue cancer. The Radiation Therapy Oncology Group (RTOG) trial 0129 demonstrated prospective evidence that HPV positivity independently predicts improved OS and progression-free survival (PFS) among patients with OSCC.9 In addition,

HPV Superficial cell layer

Intermediate cell layer Basal cell layer Basement membrane

B

A

651

Lymphocytes

C • Fig. 33.4  Base of tongue anatomy and human papillomavirus (HPV)–related head and neck squamous cell carcinoma. A, The base of tongue comprises the region posterior to the sulcus terminalis and circumvallate papillae. It includes the lingual tonsils and intrinsic and extrinsic muscles of the tongue. B, Surface epithelium of the lingual tonsils deeply invaginates into a lymphoid stroma, creating crypts that increase the surface area of the tonsil by nearly 700%. The zones of squamous epithelium—the basal, intermediate, and superficial layers—are interrupted by migrating non-epithelial cells including lymphocytes and antigenpresenting cells (APCs). Loss of structural integrity leaves the basement membrane exposed to deposition of viral particles. C, Histophotomicrograph of typical HPV-related oropharyngeal cancer, characterized by basophilic, nonkeratinizing, poorly differentiated tumor cells in a stroma heavily infiltrated with lymphocytes.

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HPV-associated oropharyngeal cancer responded favorably to RT when compared with the HPV-negative cohort. The 3-year OS for HPV-positive patients treated with concurrent chemoradiotherapy (CCRT) was 82.4% (for all patients, stages I–IV), compared with 57.1% for the HPV-negative group5 (see Fig. 33.2). Non–virally associated SCC of the base of tongue most commonly occurs in patients with significant tobacco history. Tobacco and alcohol use have a synergistic effect on upper aerodigestive tract tumorigenesis. These patients are slightly older4 and tend to have more advanced signs and symptoms at presentation. Although the risk of cervical metastasis remains high in this group, primary tumors may be more symptomatic and are frequently a cause for alarm in patients.

Staging The staging criteria and staging system for HPV-related oropharyngeal cancer recently underwent substantive modification as published in the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, thereby more accurately representing the unique biologic, clinical, and epidemiologic features of HPV-related HNSCC compared with HPV-unrelated disease (Table 33.1). The revised system was initially proposed in 2015 based on a cohort of 573 patients with HPV-related oropharyngeal squamous cell carcinoma (OPSCC) treated with radiation or chemoradiotherapy over a 10-year period and by using recursive partition analysis (RPA) and adjusted hazard ratios (AHRs) of the current TNM staging criteria to reclassify patients into stage I, II, III, or IV. Two refined staging systems (RPA stage and AHR stage) were proposed based on the current TMN metrics, both of which were superior in prognosticating oncologic outcomes when compared with the current AJCC system.14 After this discovery study, the results of a seven-center study aimed at validating this model were published, with the new HPV OPSCC staging system proposed by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S). This was essentially a modified version of the previous AHR system; the authors proposed that smoking and age should be excluded from an anatomically based prognosticating system. In addition, they found no difference in survival between T4a and T4b disease, leading the consolidation of T4 staging and ICON-S stage IV for patients with metastatic disease.15 Immunohistochemistry for p16 overexpression has emerged as an important surrogate biomarker for HPV-mediated disease; p16 is upregulated with HPV16, and oncoproteins degrade p53 and pRb, leading to HPV-mediated carcinogenesis. All oropharyngeal cancer should be tested for p16, and those cancers that do not overexpress p16 should be staged by use of the p16-negative staging system. The cut-point for determining p16 by immunohistochemistry is nuclear expression with greater than +2/+3 intensity and greater than 75% distribution, under which tumors should be staged with the p16-positive system. The primary tumor stage remains essentially the same in the modified p16-positive staging system as in the traditional

p16-negative system, with the exception that the p16-positive classification does not include a Tis category and there is not a T4b subcategory within the T4 group (Fig. 33.5). With these criteria, T1 tumors are less than or equal to 2 cm in greatest dimension, whereas T2 tumors are greater than 2 cm but less than or equal to 4 cm in greatest dimension. T1/T2 tumors by definition should be limited to the base of tongue and its intrinsic musculature and should not involve the extrinsic tongue muscles, muscles of mastication, mandible, or other pharyngeal subsites. Careful physical examination with endoscopic assistance and critical assessment of staging imaging is of paramount importance in accurately staging base of tongue carcinoma because treatment and prognosis are stage dependent. Nodal staging in the eighth edition of the AJCC Staging Manual has changed considerably, as a reflection of ICON-S data which showed that traditional N0–N2b nodal stages are homogeneous for outcome within T1 and T2 categories (creating stage I). N2c and T3 have an intermediate stage (stage II), and T4 and N3 are the least favorable group (stage III). Stage IV is reserved for distant metastasis. The revised p16-negative system includes extranodal extension (ENE) as an important prognostic variable; however, the role of ENE is less well defined in p16-positive oropharyngeal cancer and it is not a factor in staging this disease. Pathologic staging is modified for p16-positive oropharyngeal cancer to reflect data that indicate that metastatic node number, rather than ENE, laterality, or nodal size, is the prognosticator in surgically resected, neck-dissected p16-positive disease. Another finding in the surgically managed patient is that N3 disease behaves unusually well and is equivalent to N1; therefore N3 is eliminated from pN categorization. The favorable outcome for N3 is not apparent in patients treated non-surgically. Unlike with other head and neck sites, ENE does not appear to have the same prognostic significance in surgically treated patients, provided that adjuvant treatment is administered according to conventional practice. Any p16-positive cervical lymph node metastases to level II or /III from an unknown primary are staged according to the p16-positive classification. In addition, the AJCC recommends other prognostic factors be considered and recorded along with standard staging information, including Eastern Cooperative Oncology Group (ECOG)/Zubrod or Karnofsky performance measures, tobacco and alcohol use, tumor location, number and size of nodes, perineural invasion, and ENE. There is no grading system for HPV-mediated oropharyngeal tumors.

Focused Physical Examination The first step in evaluation and staging of cancer of the base of tongue remains a thorough but focused physical examination. Careful oral inspection and palpation of all subsites of the oral cavity and oropharynx should be completed with a headlight or other suitable focused light source. Care should be taken to properly dry the mucosa with gauze sponges before examination. Traction of the oral tongue anteriorly and bilaterally with a gauze sponge is particularly important to determine the anterior extent of the tumor. Retraction of the tongue

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

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TABLE American Joint Committee on Cancer Staging for Human Papillomavirus–Positive Oropharyngeal Squamous 33.1 Cell Cancer, 8th Edition

Primary Tumor (T) T0

No primary identified

T1

Tumor ≤2 cm in greatest dimension

T2

Tumor >2 cm and ≤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 tongue, medial pterygoid, hard palate, mandible or beyond. (Mucosal extension to lingual surface of epiglottis from primary tumors of the base of tongue and vallecula does not constitute invasion of the larynx.)

Regional Lymph Nodes: Clinical (cN) NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastasis

N1

One or more ipsilateral lymph nodes, none >6 cm

N2

Contralateral or bilateral lymph nodes, none >6 cm

N3

Lymph node(s) larger than 6 cm

N3

Metastasis in a lymph node ˃6 cm in greatest dimension

Regional Lymph nodes: Pathological (pN) NX

Regional lymph nodes cannot be assessed

pN0

No regional lymph node metastasis

pN1

Metastasis in 4 or fewer lymph nodes

pN2

Metastasis in more than 4 lymph nodes

Distant Metastasis (M) M0

No distant metastasis

M1

Distant metastasis

Clinical Stage When T is…

And N is…

And M is…

Then the Stage Group is…

T0, T1, or T2

N0 or N1

M0

I

T0, T1, or T2

N2

M0

II

T3

N0, N1, or N2

M0

III

T4

N0, N1, N2, or N3

M0

III

Any T

Any N

M1

IV

Pathologic Stage When T is…

And N is…

And M is…

Then the Stage Group is…

T0, T1, or T2

N0, N1

M0

I

T0, T1, or T2

N2

M0

II

T3 or T4

N0, N1

M0

II

T3 or T4

N2

M0

III

Any T

Any N

M1

IV

Registry Data Collection Variables 1. Tumor location 2. Lymph nodes 3. Perineural invasion 4. Extranodal extension 5. Smoking history From O’Sullivan B, Lydiatt WM, Haughey BH, et al: HPV-mediated (p16+) oropharyngeal cancer. In Amin M, Edge S, Greene F, et al, editors: AJCC cancer staging manual, ed 8, New York: Springer; 2017. DOI 10.1007/978-3-319-40618-3_10.

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TX

Primary tumor cannot be assessed

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor <2 cm in greatest dimension

T2

Tumor >2 cm in greatest dimension but not more than 4 cm in greatest dimension

• Fig. 33.6  Nasopharyngoscopy for visualization of the oropharynx. Note left base of tongue tumor. T3

Tumor >4 cm in greatest dimension or extension to the lingual surface of the epiglottis

N4: Single node T4a

Advanced local disease Tumor invades larynx, deep extrinsic muscles of the tongue, medial pterygoid, hard palate, or mandible

N4: Multiple nodes

T4b

Very advanced local disease Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases the carotid artery

• Fig. 33.5  Staging diagram for oropharyngeal cancer.

medially with a tongue depressor should be completed bilaterally to examine the lingual gutter and glossotonsillar sulci. The aforementioned sites should be bimanually palpated bilaterally because many base of tongue tumors are endophytic or have an endophytic component. The tonsillar fossa, anterior and posterior tonsillar pillars, and soft palate should also be carefully visually inspected and manually palpated to determine if these subsites are involved or have signs of a co-synchronous primary tumor. In-office flexible fiber-optic examination is necessary in all patients being evaluated for oropharyngeal cancer (Fig. 33.6). The nasopharynx, oropharynx, hypopharynx, and larynx should be examined in a sequential and systematic fashion.

For base of tongue cancer, this is usually the only method of visualizing the primary site. It is important to note involvement of adjacent structures from this view, particularly the glossotonsillar sulcus, inferior tonsillar poles, vallecula, and lingual epiglottis. Careful examination of the remainder of the upper aerodigestive tract is important to evaluate for a cosynchronous mucosal primary. One of the most important physical examination maneuvers is digital palpation of the base of tongue to estimate depth, thickness, surrounding tissue fixation, and laterality. HPVrelated primary tumors may be imperceptible on endoscopic examination and require digital palpation to identify. This is difficult if not impossible to perform thoroughly and effectively in the office because it elicits the patient’s gag reflex and can be quite painful or uncomfortable.

Examination Under Anesthesia or Operative Endoscopy Although not always necessary, examination under anesthesia with operative rigid endoscopy serves many purposes. First, it allows for comprehensive digital palpation of the oropharynx, which in many patients cannot be completed without general anesthesia. Second, the use of a rigid laryngoscope allows for direct biopsy of the lesion to obtain a tissue diagnosis. Although this can be done in the office with a flexible endoscope with an internal port, it may be cumbersome for the surgeon and uncomfortable for the patient. In addition, obtaining a positive biopsy with flexible wire tissue forceps can be challenging with endophytic tumors because the base of tongue needs to be “unroofed” in order to enter the tumor. Rigid endoscopy also allows for palpation of the tumor and base of tongue under direct vision with use of a suction cannula or cup forceps. This is of particular importance when evaluating patients for transoral resection. In patients with T1 and small T2 base of tongue tumors deemed transorally resectable with robotic assistance, operative endoscopy and tumor mapping may be performed immediately before surgical extirpation with the use of frozen pathology if necessary.

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

655

in select cases because it may better delineate cancer in the base of tongue from surrounding unaffected soft tissue and does not require the use of iodinated intravenous contrast in patients with renal failure or iodine allergies. The sensitivity and specificity are comparable in detecting cervical adenopathy, although there is a wide range in the published literature.16 Both are superior to physical examination alone.

Positron Emission Tomography–Computed Tomography

• Fig. 33.7 Computed tomography (CT) scan of neck with contrast for staging of the neck in patient with T1N2cM0, stage IVA squamous cell carcinoma of the base of tongue. Note bilateral cervical lymphadenopathy.

Rigid esophagoscopy and bronchoscopy may also be used at this stage to assess for co-synchronous primary tumors, although positron emission tomography–computed tomography (PET-CT) has replaced elective panendoscopy for oropharyngeal cancer in our practice. Suspicious lesions or those with fludeoxyglucose F 18 (FDG) uptake on PET-CT warrant further evaluation with esophagoscopy or bronchoscopy and biopsy. Evaluation of the neck also begins with physical examination and comprehensive palpation of the regional lymphatics. Although computed imaging techniques are more sensitive in detecting clinical metastatic lymphadenopathy, palpation allows the oncologist to characterize involved lymph nodes. The degree of fixation to the underlying tissue and overlying skin is helpful in neck dissection planning.

Imaging Computed Tomography and Magnetic Resonance Imaging High-definition computed tomography (CT) scan or magnetic resonance imaging (MRI) is instrumental in the staging process for most head and neck cancers. These imaging techniques allow the oncologist to assess the extent of the primary tumor and, combined with proper physical examination, are necessary for the accurate staging of base of tongue carcinoma. For T1/T2 base of tongue SCC, these studies allow for three-dimensional tumor mapping and are useful in determining if the disease is resectable via a transoral roboticassisted approach. Assessment of the regional lymphatics via CT or MRI is also an important component in clinically staging the neck. Although either study may be used, contrast-enhanced CT is the preferred method for most cases at our cancer center because it is more cost-effective, faster, and better tolerated by most patients (Fig. 33.7). MRI does have a distinct advantage

Positron emission tomography (PET) is useful in identifying metabolically active tissues in the work-up and staging for head and neck cancer. Combined with traditional CT scan, PET-CT offers the advantage of fusing anatomic tomographic images to correspond to areas of FDG uptake. Although perhaps best suited for advanced-stage disease and assessment of regional and distant metastasis, PET has an important role in patients with oropharyngeal cancer as an aid in the detection of the primary tumor or in cases of an unknown primary. The majority of patients with HPV-related T1/T2 base of tongue SCC will have a neck mass at presentation. A portion of these patients will have no obvious lesion on clinical examination or CT or MRI. Although fine-needle aspiration (FNA) of the metastatic lymph node can confirm a cytologic diagnosis and even HPV status, detecting the primary tumor may prove to be difficult. PET-CT may reveal a hypermetabolic focus in the oropharynx where no obvious or subtle structural abnormality exists. This allows for PET-directed biopsies instead of diagnostic tonsillectomy and multiple blind biopsies. Although lymphoid tissue in the tonsil and base of tongue, as well as pharyngeal muscle, may demonstrate some baseline FDG uptake, the keen eye of an oncologist can pick up subtle differences between left and right. Careful interpretation of PET-CT scan in the search for an occult primary tumor may guide therapy (Fig. 33.8). False-positive PET imaging is a well-recognized phenomenon in association with acute inflammation or tonsillitis. However, false-negative findings can also occur, particularly within necrotic lymph nodes, which are commonly associated with HPV-related oropharyngeal cancer (Fig. 33.9). HPV-related oropharyngeal cancer has somewhat less predictable patterns of distant metastases when compared with its HPV-negative counterpart.17 Although the presence of distant metastases at initial presentation is uncommon, PET-CT remains valuable in detecting stage IVC disease, particularly in cases of extrapulmonary metastasis. In addition, this provides a baseline study for post-treatment comparison. We routinely advocate for combined PET with high-resolution iodinated contrast-enhanced CT for initial staging of patients with T1/ T2 base of tongue cancer with any cervical metastasis (stage III and IV disease).

Ultrasound-guided Fine-Needle Aspiration Although ultrasound alone has limited value in staging base of tongue carcinoma, ultrasound-guided FNA is a valuable tool in characterizing the cervical lymphatics. A 2007 meta-analysis of 17 articles and 25 data sets comparing various methods of lymph node metastasis detection demonstrated that

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B

D

C • Fig. 33.8  Human papillomavirus–related base of tongue cancer in 48-year-old with T1N2bM0, stage IVA. Note that computed tomography (CT) evaluation and nasopharyngoscopy failed to detect primary lesion. However, on positron emission tomography–computed tomography (PET-CT) imaging, the small right base of tongue primary was noted to be embedded within hypertrophied lingual tonsillar tissue, and the patient was treated with transoral robotic surgery. A, Preoperative CT scan, axial view. B, Preoperative PET-CT scan, axial view. C, Preoperative CT scan, sagittal view. D, Postoperative CT scan, sagittal view.

ultrasound-guided FNA had the highest diagnostic odds ratio when compared with ultrasound alone, MRI, or CT scan. This meta-analysis also showed that specificity did not suffer with increased sensitivity when ultrasound-guided FNA was used to detect metastatic lymphadenopathy. Although the sensitivity of this modality had a wide range depending on the study (48–90%), specificity remained at 98–100%.18 This requires an experienced and suitable sonographer or operator because careful sonographic evaluation of suspicious-appearing nodes as well as accurate needle aspiration are necessary in producing a representative sample. This technique is not practical in comprehensive clinical evaluation of the neck because the examinations are lengthy and somewhat invasive if procedures at multiple sites or multiple biopsies are to be performed. It is best suited to confirm a positive diagnosis of SCC in a patient with an obvious base of tongue mass to potentially obviate the need for surgical endoscopy and biopsy under anesthesia.

Pretreatment Patient Discussion Once all the relevant diagnostic data have been obtained and staging studies have been completed, pretreatment consultation with the patient and his or her support system is appropriate. At our cancer center this consultation takes the form of a multidisciplinary forum, which requires the input of the surgeon, radiation oncologist, dental oncologist, medical oncologist, speech-language pathologist (SLP), dietitian, social worker, and nurse navigator. The National Comprehensive Cancer Network (NCCN) has guidelines and algorithms published annually based on the available data to help guide treatment for OSCC; these recommendations are strongly considered and generally followed. However, special circumstances such as poor performance status may necessitate deviation from NCCN guidelines on occasion. Clinical trials should be a priority in all patients with HNSCC, particularly those with advanced-stage disease.

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

A

C

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B

D • Fig. 33.9  T2N2 base of tongue squamous cell carcinoma (SCCA) in a 58-year-old man. Note falsenegative finding on positron emission tomography–computed tomography (PET-CT) image of the metastatic lymph node demonstrated on contrasted computed tomography (CT) scan. A, CT scan of neck with contrast demonstrating primary lesion in base of tongue, axial view. B, CT scan of neck with contrast demonstrating metastatic lymph node in level II of the right neck, axial view. C, PET-CT, axial image. D, PET-CT, axial image.

Principles of Management—Surgery Versus Primary Radiotherapy or Chemoradiotherapy Current NCCN guidelines advocate single-modality therapy for T1/T2 base of tongue squamous cell carcinoma (SCCA) without evidence of cervical metastases. This may include definitive radiation or surgical resection with or without neck dissection. At our institution, the majority of T1/T2 base of tongue carcinomas, over 90% of which are HPV positive, are treated primarily with TORS followed by risk-adapted adjuvant therapy. Patients also receive simultaneous, elective, selective level II–IV neck dissection at the time of TORS. Patients with high-risk features, such as bulky neck disease (N2c or N3)

or obvious extracapsular nodal extension, are usually treated with definitive chemoradiation (Fig. 33.10). Operative patients are currently stratified into risk groups based on various histopathologic features related to margin status, cervical metastasis, extracapsular extension, perineural invasion, or lymphovascular space invasion (Table 33.2). Lowrisk patients have negative resection margins and N0–N1 disease without adverse histopathologic features and are observed after surgery; intermediate-risk patients have negative resection margins and more than one metastatic lymph node, perineural invasion, or lymphovascular invasion and are treated with adjuvant RT to 60 Gy; high-risk patients are those with positive resection margins or extracapsular extension and are treated with adjuvant radiation to 66 Gy with concurrent cisplatin. Patients

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A

B

C • Fig. 33.10 A 59-year-old man with a diagnosis of a stage IVA T1N3M0 right base of tongue squamous cell carcinoma with bulky adenopathy treated with induction chemotherapy followed by concurrent chemoradiotherapy with cetuximab and radiation to 7000 cGy. A, Pretreatment CT scan of neck. B, Frontal view of patient. C, Intensity-modulated radiotherapy treatment fields.

with multiple cervical lymph node metastases or level IV or V adenopathy are also considered for adjuvant chemoradiotherapy because they may have a higher risk of treatment failure.19 Since the 1990s, the mainstay of treatment for T1/T2 base of tongue SCC has been definitive RT or definitive concurrent chemoradiotherapy. Compared with traditional open surgical

approaches that employ mandibulotomy or transcervical pharyngotomy, definitive radiation was better tolerated with lower short-term morbidity, but with similar oncologic control. The paradigm shift toward “organ preservation” with non-surgical primary management of early-stage oropharyngeal cancer resulted in part from results of the Veterans Administration laryngeal cancer

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

TABLE Postoperative Risk Stratification for Human 33.2 Papillomavirus–Positive Oropharynx Squamous

Cell Carcinoma

Low Risk Intermediate Risk

High Risk

T

T1/T2

T3/T4

Any

N

N0/N1

N2a/b/c

N3 or >4 nodes

Margins

Negative

Negative/close

Positive

ECE

Negative

Negative or micro <1 mm

Positive

PNI

Negative

Positive

Any

LVI

Negative

Positive

Any

ECE, extracapsular extension; PNI, perineural invasion; LVI, lymphovascular invasion.

trial, RTOG 91-11. However, since U.S. Food and Drug Administration (FDA) approval of TORS in 2009 for surgical treatment of oropharyngeal cancer, an increasing number of patients have been treated with a transoral surgical approach in an effort to tailor and de-escalate therapy where possible. There are now 2- to 5-year follow-up data indicating that locoregional control with TORS and risk-adapted adjuvant therapy is at least not inferior to control with definitive radiation or chemoradiation for the treatment of HPV-associated T1/T2 base of tongue SCC.20–23 Although survival outcomes are excellent with either modality, the major benefit of surgery in this setting is that it allows the treatment to be tailored based on histopathologic interrogation and risk stratification, thereby eliminating the need for RT or chemotherapy in some patients and potentially resulting in a lower incidence of dysphagia and long-term gastrostomy tube dependence as well as better quality of life indices.21,24 Furthermore, early data regarding the use of the da Vinci surgical robot (da Vinci Surgical System, Intuitive Surgical, Sunnyvale, California) for oropharyngeal cancer resections demonstrate safety with low morbidity and mortality, which continue to improve as surgeon experience and training progress.20,25–28 Since the initially published data demonstrating improved OS and favorable treatment response of HPV-positive oropharyngeal cancer compared with HPV-negative cohorts, oncologists have expressed interest in de-escalating therapy to reduce short- and long-term morbidity associated with treatment. The use of TORS for early-stage OSCC has almost certainly driven this enthusiasm, as early data suggested improved quality of life when compared with definitive non-surgical therapy. Several clinical trials—both surgical and non-surgical—are currently accruing patients in an attempt to answer that question. Currently, the treatment for HPV-positive and HPV-negative T1/T2 base of tongue SCC is identical outside of a clinical trial setting.

Radiation and Chemotherapy Before the advent of TORS, in the last two decades, RT was the backbone of treatment for most oropharyngeal cancer. There has not been a randomized prospective clinical trial comparing surgery versus radiation for base of tongue cancer. A cooperative group trial aiming to compare RT and transoral resection of

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HPV-negative oropharyngeal cancer, RTOG 1221, was terminated owing to poor accrual. To help compare the two outcomes, Parsons and colleagues published a 30-year retrospective review of 51 studies reporting on 6400 patients with OSCC treated with surgery with or without RT, or primary radiation with or without neck dissection.29 The majority of these patients underwent open surgical resection with mandibulotomy and radical neck dissection followed by possible adjuvant RT, or conventional external beam RT with possible salvage radical neck dissection. Intensity-modulated radiotherapy (IMRT), TORS, and advanced microsurgical reconstruction were not available during the three decades before this review. The results for patients with SCC of the base of tongue who underwent surgery with or without RT, and RT with or without neck dissection, respectively, were demonstrated to be nearly equal with regard to local control (79% vs. 76%; P = 0.087); locoregional control (60% vs. 69%; P = .009); 5-year survival (49% vs. 52%; P = .2); and 5-year cause-specific survival (62% vs. 63%; P = .4). However, there were significant differences between the groups with respect to severe complications (32% vs. 3.8%; P = .001) and fatal complications (3.5% vs. 0.4%; P = .001), favoring the cohort that underwent RT with or without neck dissection. The authors concluded that non-operative therapy was preferable to operative therapy for oropharyngeal cancers, regardless of stage, because it was associated with significantly lower morbidity and mortality. RT for early-stage base of tongue cancer may be used as single-modality therapy in the absence of clinically apparent cervical metastases and is routinely used in the adjuvant setting after surgical resection of an intermediate- to high-risk base of tongue carcinoma. Indications for RT in the definitive setting include patients who are not medically fit for surgery and cases in which surgery may result in trimodality therapy (predicted difficulty obtaining clear margins or radiographs suspicious for extranodal tumor extension).

Principles of Radiotherapy IMRT is now the standard of care for treatment of most head and neck malignancies, including the base of tongue. Advanced imaging techniques, cone-beam CT, and computed localization allow for precise delivery of radiation with the ability to minimize collateral tissue damage. Standard fractionation is used in the majority of patients, with once-daily treatments, 5 days per week, with treatment breaks as needed because of acute toxicity. Altered fractionation has been studied prospectively in advanced head and neck cancer and T2N0 base of tongue cancer. RTOG trial 9003 randomized patients with stage II–IV head and neck cancer to a control standard fractionation arm and three arms of altered fraction radiation—hyperfractionation, accelerated fractionation with continuous treatment, and accelerated fractionation with split. Final results of this trial published in 2014 demonstrated that patients undergoing hyperfractionation (81.6 Gy/68 twice-daily fractions) had improved survival and locoregional control when compared with standard fractionation (70 Gy/35 daily fractions) with a hazard ratio of 0.79. This translates to a reduction in locoregional failure rate by 19%.30 Nevertheless, altered fraction therapy is seldom used in early-stage oropharyngeal cancer because locoregional control is excellent (88–98%) with standard fractionated IMRT alone.31,32

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In a typical IMRT plan for base of tongue cancer, known tumors, including the primary and metastatic adenopathy, are treated to 70 Gy. The remainder of the node-positive neck is treated at 59.4–63 Gy; a clinically negative neck is treated prophylactically at 54–56 Gy. This is done in 33–35 fractions depending on final dosage. Indications for RT in the adjuvant postoperative setting include advanced primary lesions (pT3/pT4), N2 or greater nodal disease, nodal disease in levels IV or V, perineural invasion, or lymphovascular invasion. The primary and involved neck are treated to 60 Gy. If there is uninvolved neck, this is treated to 54–56 Gy. Positive margins or extranodal tumor extension are high-risk adverse pathologic features and are treated to 66 Gy. Furthermore, these patients benefit from the addition of platinum-based chemotherapy concurrently with radiation. The results of two large cooperative group trials, European Organisation for Research and Treatment of Cancer (EORTC) trial 22931 and RTOG trial 9501, published in 2004, comparing postoperative radiation and postoperative concurrent chemoradiation for advanced head and neck cancer demonstrated a survival benefit in the concurrent chemoradiation arm.33,34 A 2005 post hoc analysis of the paired studies teased out that a select group of patients, namely those with ENE or positive surgical margins, benefitted from the addition of platinum-based chemotherapy, with an absolute survival benefit of 8%.35 This led to the NCCN recommendation for addition of cisplatin to radiation in the adjuvant setting for those particular high-risk features.

Surgery There is a wide variety of surgical approaches to the base of tongue, but they can be broken down into two distinct classifications—open versus transoral. Although many T1/T2 cancers of the base of tongue may be treated via transoral approaches, such as TORS or transoral laser microsurgery (TLM), some tumors still require wide, open access via more traditional approaches. These include access mandibulotomy, transcervical lateral pharyngotomy, or transcervical suprahyoid pharyngotomy. The transcervical lingual degloving or “pull-through” approach is generally reserved for larger tumors requiring total or subtotal glossectomy. Management of the airway is critical for all operations involving the upper aerodigestive tract, and surgery of the base of tongue is no exception. The tongue, rich in vascularity and lymphatics, is prone to significant edema after instrumentation. Furthermore, the use of transoral retractors such as the FeyhKastenbauer, McIvor, Crowe-Davis, or other mouth gags for extended periods of time may result in significant venous congestion of the tongue. For patients undergoing transoral resection for base of tongue cancer, endotracheal intubation is preferred. It is imperative to communicate with the anesthesia team before induction and formulate an intubation plan. Although intubation may be accomplished via the nasal or oral route, our institutional preference is oral intubation with a reinforced or armored endotracheal tube. This is secured to the buccal mucosa opposite the side of the tumor by using heavy silk horizontal mattress sutures. In general, T1/T2 tumors of the base of tongue are not obstructive, but if clinic fiber-optic examination demonstrated airway compromise, awake fiber-optic intubation may

be indicated. After base of tongue resection, clinical judgment dictates whether or not it is preferable to leave the patient intubated and transfer him or her to the intensive care unit. In our experience, the majority of patients can be safely extubated after TORS. However, if tongue edema and venous congestion are substantial, we will leave the patient intubated overnight. Extubation on postoperative day 1 is routinely accomplished after the patient passes a cuff leak test and spontaneous breathing trial. For patients undergoing open surgery for base of tongue cancer, tracheostomy is the preferred airway. Whether this is preceded by endotracheal intubation or performed as an awake tracheostomy is dictated by the amount of airway compromise from the tumor. Nonobstructive base of tongue cancers are generally amenable to oral endotracheal intubation before tracheotomy. Almost all patients undergoing open base of tongue resection require flap reconstruction of the defects, particularly if they have been previously irradiated or have undergone transcervical pharyngotomy. This necessitates tracheotomy for perioperative airway edema, but most patients can be decannulated before discharge from the hospital. Patients undergoing total glossectomy and flap reconstruction may require long-term or permanent tracheostomy or laryngectomy, in the case of chronic aspiration.

Transoral Robotic Surgery Transoral robotic-assisted base of tongue resection has become the preferred minimally invasive method for the surgical treatment of T1/T2 tonsil cancers at high-volume institutions. Compared with traditional transoral techniques, such as TLM, TORS offers several potential advantages including high-resolution, three-dimensional operative view, improved operative precision, movement scaling, and dynamic multiplanar and true 360-degree rotational motion.36,37 Although this technique has an associated learning curve, complication rates are inversely related to surgeon experience. A 2013 survey of 45 U.S. TORS surgeons reported a 0.3% mortality rate, all related to postoperative hemorrhage, with a statistically significant decrease in complication rate with surgeon operative volume greater than 50 cases.38 After securing the airway as outlined earlier, room setup, anesthesia collaboration, and robotic docking are critical to the success of a TORS operation39 (Fig. 33.11). The table is turned 180 degrees away from the anesthesiologist, arms are tucked, and head is positioned on a Mayfield horseshoe headrest to allow for ideal neck extension and linear access to the oropharynx. The upper teeth are protected with a soft tooth guard, and an oropharyngeal retractor is placed under headlamp visualization. We prefer the Feyh-Kastenbauer-WeinsteinO’Malley (FK-WO) retractor because it is maximally adjustable (Fig. 33.12). The ability to control the pitch and depth of the retractor is particularly helpful in accessing the base of tongue. A variety of tongue blades for the FK-WO are available. Once the FK-WO retractor is adequately positioned, the retractor is placed into suspension using StrongArm devices (MediFlex, Islandia, NY) latched to the operative table (Fig. 33.13). The da Vinci Si robot (Intuitive Surgical, Sunnyvale, CA) is then docked to the patient at a 30- to 45-degree angle. We prefer a 30-degree endoscope through the central cannula and 5-mm EndoWrist (Intuitive Surgical, Sunnyvale, Calif.) monopolar cautery and Maryland dissectors through the

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

EndoWrist ® instruments are designed with seven degrees of freedom and mimic the dexterity of the human hand and wrist

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Patient cart

Anesthesiologist

Vision cart Assistant Nurse

Surgeon uses open-surgery hand movements that are precisely replicated in the operative field by the EndoWrist instruments

Surgeon at console

• Fig. 33.11  Transoral robotic surgery room setup. (From Park ES, Shum JW, Tuan GB, et al. Robotic s­ urgery: a new approach to tumors of the tongue base, oropharynx, and hypopharynx. Oral Maxillofac Surg Clin North Am. 2013 Feb;25[1]:49–59.)

• Fig. 33.13  Robotic arm setup for transoral robotic-assisted oropharyngectomy.

• Fig. 33.12  Instrumentation for transoral robotic surgery.

working cannulas. Care should be taken to position the distal ends of the cannulas just outside the oral introitus with sufficient inter-instrument width to avoid collisions during the operation. A bedside assistant is armed with two tonsillar suction catheters to evacuate smoke, blood, and saliva as well as to retract soft tissue for the console surgeon (Fig. 33.14).

Because early-stage base of tongue cancers may be small and difficult to visualize, it is oncologically favorable to resect the hemi– base of tongue as an entire unit to ensure en bloc resection. The operation begins with a horizontal incision, using monopolar cautery at the level of the circumvallate papilla—this should be positioned just posterior to the edge of the tongue blade (Fig. 33.15).

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A

B • Fig. 33.14  View stations for transoral robotic surgery. A, Assistant’s view.; B, Operating surgeon at the robotic console.

Hyoglossus m. External carotid a. Dorsal lingual a. Glossopharyngeus a. Palatopharyngeus a. Superior constrictor a.

Foramen cecum Lingual tonsil

Upper jaw retractor Robotic arm (grasper)

Pharyngeal tonsil Tumor Vallecula Uvula

Camera

Tumor

Tongue retractor

Vellecula

Robotic arm 2 (electrocautery)

A

B Tumor retracted and excised

Superior longitudinal muscles of tongue Floor of dissection

Vertical and transverse muscles of tongue

Cut edge of genioglossus m.

Lingual artery, vein and nerve Genioglossus m.

Geniohyoid m.

C

D • Fig. 33.15  Surgical view for transoral robotic-assisted base of tongue resection and oropharyngectomy. A, Intraoperative view. B, Sagittal view. C, Tumor resection. D, Postoperative view.

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

Dissection is carried medially to the midline and laterally to the glossotonsillar sulcus. The cut edge is grasped with Maryland dissectors, and the plane of dissection is sharply deepened in a broad front by using a deliberate sweeping motion to open the optical space between the specimen and tongue, as well as to cauterize the highly vascular muscle bed. As dissection proceeds posteriorly, the specimen is grasped and retracted posteriorly and superiorly to allow for adequate visualization. Dissection is carried posteriorly to the level of the vallecula. The armored endotracheal tube is an excellent guide to approximate depth and anteroposterior position as it passes just behind the epiglottis. Laterally, the lingual artery or its branches may be encountered; the application of hemoclips by the bedside assistant may be required for control. A 5-mm endoscopic clip applier is preferable in this situation because it allows for 360-degree motility. The specimen is then cleaved off through the mucosa of the vallecula and carefully delivered to the bedside assistant while correct orientation is maintained. At our institution, the entire specimen is oriented and sent to the pathology department fresh for specimen-driven frozen-section margin analysis. If close or positive margins are identified, these areas are re-resected to negative margins. Concomitant elective or therapeutic neck dissection has been shown to be safe, with less than a 5% rate of persistent pharyngocutaneous fistula, and is our preferred method for surgical treatment.25,27,40 Our institutional preference is to perform TORS and neck dissection during the same operation, in that order; however, for large tumors involving the glossotonsillar sulcus, neck dissection can be performed immediately before TORS resection in order to ligate the lingual artery or gain proximal carotid control. Our experience with T1/T2 tumors is that this is not usually required and that operative time may be reduced when the primary is resected first because the neck dissection can commence while one waits for margin status from the pathology department. The extent of neck dissection is not universally agreed on, but most U.S. centers have gone to use of a level II–IV selective neck dissection, which has been shown to be safe and efficacious and to minimize morbidity (Fig. 33.16). Although we initially performed comprehensive neck dissection, we have evolved to use of a small-incision, level II–IV selective neck dissection unless there is clinical or radiographic evidence of level I or V lymph node metastasis (Fig. 33.17).

Salvage Surgery Before the era of non-surgical organ-preserving therapy, earlystage base of tongue carcinomas were routinely treated with open surgical approaches. Although locoregional control for T1/ T2 oropharyngeal carcinoma is excellent with this approach, it does not come without morbidity. The use of access mandibulotomy or transcervical pharyngotomy is associated with pharyngeal leaks or fistulas, mandibular non-union, osteonecrosis, and facial incisions or scars, and these procedures more likely to require vascularized flap reconstruction when compared with transoral approaches, although many retrospective reviews have suggested that these approaches are well tolerated and accepted by patients.41–43 These techniques are now primarily reserved for advanced-stage oropharyngeal cancer in which organ-sparing therapy is contraindicated or in the salvage setting for treatment

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failure. As stated previously, it is our practice to employ transoral minimally invasive approaches for early-stage base of tongue cancer for patients who may require only single-modality therapy or surgery with adjuvant RT alone. The role for open surgery for T1/T2 base of tongue carcinomas is limited to patients in whom non-surgical treatment has failed or patients with absolute contraindications to RT or chemoradiotherapy. Both transcervical and transmandibular open approaches to the base of tongue allow for wide access, en bloc resection, and ability to functionally reconstruct the pharynx with free tissue transfer; however, decreased rates of postoperative fistula, temporomandibular joint dysfunction, and esthetic morbidity have been reported with transcervical approaches.44,45 As described earlier in this manuscript, tracheostomy is the airway of choice when transcervical or transmandibular surgery is combined with free flap reconstruction. Unlike TORS approaches, open approaches routinely require the creation of a sizable pharyngo-cervical communication. Historically, these were managed with regional flaps, such as the pectoralis major myocutaneous flap; however, free flap reconstruction provides excellent results with regard to functional restoration of the base of tongue, prevention of aspiration, and separation of the pharyngeal and cervical compartments.

Transcervical Pharyngotomy The majority of patients undergoing this operation will require elective or therapeutic neck dissection, so it is preferable to complete this immediately before accessing the pharynx. This allows for proximal vascular control and a surgical field that is clear of lymph node–bearing fibro-adipose tissue. The suprahyoid musculature is sharply separated from the hyoid bone, working from the midline out laterally. Completion of the neck dissection also allows for prior identification of the hypoglossal nerves, which may be prone to injury adjacent to the greater cornu of the hyoid bone. Once the submucosal surface of the pharynx is visualized from the cervical approach, a long toed-in Langenbeck retractor is placed into the vallecular space transorally. A suprahyoid pharyngotomy is created with cautery against the tip of the retractor, and the oropharynx is entered. Deaver or Sewell curved retractors are placed superiorly and inferiorly through the pharyngotomy to identify the base of tongue tumor (Fig. 33.18). A central segment of hyoid bone can be excised or divided for improved access. In addition, separation of the inferior constrictor from the thyroid cartilage and extension of the pharyngotomy laterally toward the piriform recess may be required to enter the pharynx laterally for wider exposure46 (Fig. 33.17B). This is particularly helpful in larger tumors with hypopharyngeal involvement. At this point, the specimen can be carefully grasped and resected with sharp dissection using monopolar cautery. The lingual artery is commonly encountered and should be ligated. Patients with larger T2 tumors or who have a previous history of radiation should undergo reconstruction with vascularized tissue, preferably a radial forearm free flap, to provide an adequate tongue mound to reduce aspiration and to close the pharyngocervical communication with reliable tissue. Smaller tumors may be left to heal by secondary intention, but impeccable closure of the pharyngotomy with local tissue rearrangement is critical in reducing the rate of salivary leaks and fistulas. This

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A

B

C

D

F

E

G • Fig. 33.16  A 68-year-old male with pT2N2bM0, stage IVA, human papillomavirus (HPV)–positive squamous cell carcinoma of the left base of tongue treated with transoral robotic surgery and risk-adapted adjuvant radiation therapy. A, Pretreatment computed tomography (CT) scan of neck with contrast demonstrating base of tongue tumor, axial view. B, Pretreatment CT scan of neck with contrast demonstrating metastatic lymph node, axial view. C, Pretreatment positron emission tomography–computed tomography (PET-CT) scan. Carcinoma was initially staged as cT2N1M0, stage III. D, Nasopharyngoscopy revealed left base of tongue tumor. E, Intraoperative view after transoral robotic-assisted oropharyngectomy. F, Intraoperative view of simultaneous selective neck dissection, level II–IV, preserving submandibular gland, spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle. G, Resection specimens, which generated negative resection margins and three positive lymph nodes, resulting in upstaging to pT2N2bM0, stage IVA.

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H

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I • Fig. 33.16, cont’d  H, Adjuvant radiation dosimetry and treatment fields. I, Appearance of patient 1 year after completion of treatment.

is accomplished by closing the pharyngeal mucosa with heavy slow resorbing sutures in large bites around the base of tongue and circumferentially around the hyoid. The lateral portion of the pharyngotomy in the hypopharynx should be closed with inverting mattress sutures in a Connell fashion. The suprahyoid and infrahyoid musculature can be raised as pedicled flaps to bolster to suture lines as a second layer of closure.

Transmandibular Approach Similar to the transcervical approach, the transmandibular approach is best accomplished after completion of the regional lymphadenectomy (Fig. 33.19). The difference is in incision design, because this procedure will require a cutaneous lipsplit. A fine-tipped marking pen is used to design a lower-lip midline split with a 90-degree stair-step at the vermillion border to help reorient the lip on closure. This is carried vertically to the labiomental crease and then followed in a wide semicircle around the chin pad back to the midline and the cervicomandibular junction. We prefer a modified Z-plasty design on the anterior neck to break up the scar and reduce the length of incision against lines of resting tension. This is then carried horizontally through a natural neck crease posteriorly past the border of the sternocleidomastoid. During completion of the skin incision, the sharp angles designed in the lip and anterior neck can be accomplished by “stabbing” a No. 15 blade through each corner, with the back

side of the blade creating the angle. This permits precise incisions, which will be important for esthetic closure. Skin flaps are elevated in a subplatysmal plane in the neck and full thickness overlying the chin. At this point, a mandibular vestibular mucosal incision should be designed based on the location of the planned mandibulotomy. Preoperative orthopantomogram is useful in selecting the osteotomy location. Midline or paramedian osteotomy is dictated by interdental spacing; care must be taken to avoid injury to dental roots. The gingival incision should be placed two teeth away from the planned osteotomy to avoid a suture line over the bone closure. This is carried through the vestibule on the ipsilateral side of the tumor, leaving an adequate cuff of unattached gingiva to close to. Subperiosteal dissection is completed on the buccal surface of the mandible to allow for plate adaptation. It is not required to develop a large cheek flap because this does always not improve access to the tongue base and unnecessarily compromises the periosteal blood supply to the mandible. The planned mandibulotomy is scored with a reciprocating saw, and plates are prebent to the mandible. Arbeitsgemeinschaft für Osteosynthesefragen (AO) principles are followed for mandibular osteosynthesis, which requires an inferior border plate and superior tension band. Bicortical screw fixation at the inferior border is preferred, with a four- to six-hole plate and monocortical fixation at the tension band four-hole miniplate to avoid dental injury. It is imperative to carefully and

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B A

Nodes Malignant node (JD nodal chain)

Metastic nodes and surrounding / investing fibroelastic tissue dissected posteriorly to anteriorily

Fibroadipose tissue

C

D • Fig. 33.17 Surgical management of the neck for oropharyngeal cancer: selective neck dissection, clearing levels II–IV. A, Incision design. B, Small incision design in prominent neck crease, intraoperative view. C, Superior and inferior skin flaps elevated in subplatysmal plane exposing fibro-adipose lymphatic-containing tissue (FALT) from the digastric muscle superiorly, the clavicle inferiorly, the trapezius posteriorly, and the thyroid cartilage anteriorly. D, FALT from levels II, III, and IV is mobilized off the paraspinal musculature, over the internal jugular vein and carotid artery, with preservation of the cervical rootlets and spinal accessory nerve.

accurately bend the plates to follow the contours of the mandible because even a small amount of plate torquing and elastic deformation may result in a malocclusion. Once the plates have been adapted and the mandible has been pre-drilled, the plates and screws are oriented and set aside. The osteotomy is completed with a reciprocating saw from the alveolus to the inferior border. If the interdental space is tight, it is advisable to compete the superior aspect of the osteotomy with a small sharp osteotome. Once the mandible is split, dissection proceeds through the floor of the mouth toward the base of tongue. A cuff of lingual mucosa should be left attached to the mandible if oncologically

permitted to aid in closure. The floor of mouth muscles are released and portions of them may be included in the specimen for margins. A cuff of mylohyoid may be left attached to the lingual aspect of the mandible for later re-suspension. During this maneuver, the lingual nerve may be dissected free and protected as it crosses from lateral to medial into the body of the tongue. As the dissection approaches the base of tongue mass, 1- to 1.5cm oncologic margins are observed. The mandible is retracted bilaterally with the aid of large self-retaining Adson-Beckmann retractors or an assistant with a bone hook. Countertraction on the tongue is best accomplished with a penetrating towel clamp through the oral tongue. As dissection and resection proceeds

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

Stylohyoid m. Posterior belly digastric m

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Hypoglossal n. Platysma incision and retracted

Spinal accessory n.

Scm retracted

Tumor bed splenius capitis

E

F

G

• Fig. 33.17, cont’d  E, FALT from levels II–IV is delivered en bloc with preservation of the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle. F, Intraoperative view after removal of FALT. G, Pathologic specimen.

posteriorly, the medial pterygoid is released and the working space opens so complete visualization of the base of tongue and oropharynx is possible. The lingual artery is ligated (or may have been previously ligated during neck dissection) and the tumor is resected with monopolar cautery. Careful visualization and digital palpation are of utmost importance during tumor resection to ensure adequate gross margin status. Reconstruction of the tongue base is often necessary after resection, particularly in the salvage setting. For T1/T2 tumors, the radial forearm flap provides adequate soft tissue bulk to form a tongue mound. Thin patients with large T2 tumors may require thicker tissue such as an anterolateral thigh free flap or pectoralis major myocutaneous flap. Patients undergoing mandibulotomy and resection for primary treatment of early-stage tongue base carcinoma can simply undergo reconstruction with an oral tongue sliding flap, or foreshortening of the oral tongue to close the base of tongue defect. The remainder of the wound is closed in layers, with care taken to suspend the mylohyoid and hyoid bone.

Rationale for Elective Regional Lymphadenectomy SCC of the base of tongue has a high propensity for cervical metastasis. In HPV-driven carcinomas, at presentation the majority of patients have advanced-stage disease due to clinically positive adenopathy.47 T1/T2 base of tongue carcinomas with cN0 necks have occult metastasis rates ranging from 21% to 26%.47a,48 For this reason, clinically N0 patients being treated with a surgery-driven approach should be considered for at least ipsilateral elective selective neck dissection to levels II–IV.8,9 A retrospective analysis of 352 patients undergoing bilateral neck dissection for OSCC demonstrated a 28% incidence of pathologic bilateral cervical metastasis for T1/T2 base of tongue primaries (n = 78).49 This is likely biased based on surgeon selection of “high-risk” patients being prescribed bilateral rather than ipsilateral neck dissection and does not take into account early-stage tumors that encroached on the midline. These data also suggest that

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base of tongue tumors were more likely to have bilateral cervical metastases when compared with tonsillar cancers (P = .004), but this has never been studied in a well-powered prospective clinical trial. Based on the current data, there is no absolute recommendation for contralateral elective neck dissection in base of tongue tumors that do not encroach on the midline.

Postoperative Care

• Fig. 33.18  Lateral pharyngotomy, intraoperative view.

A

After TORS base of tongue resection, patients will receive a nasogastric (NG) feeding tube and remain intubated overnight for airway protection. If not otherwise contraindicated, patients will receive 125 mg of intravenous methylprednisolone and 80 mg of intramuscular methylprednisolone depot to aid in alleviation of surgical edema. Maintenance fluids are initiated, taking care not to over-resuscitate. The head of bed is elevated 30 degrees or more to allow for dependent drainage, and most patients can be extubated within 24 hours if they pass

B • Fig. 33.19  A 48-year-old male with cT2N2cM0, stage IVA human papillomavirus (HPV)–negative squamous cell carcinoma of the base of tongue treated with primary chemoradiation. Twelve months after treatment, patient developed local recurrence and underwent salvage oropharyngectomy via mandibulotomy approach and reconstruction using a radial forearm free flap. A, Pretreatment positron emission tomography–computed tomography (PET-CT) demonstrating 4 cm ulcerated base of tongue tumor. B, Intensity-modulated radiotherapy (IMRT) plan.

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

a spontaneous breathing trial and cuff leak test. Tube feeds are initiated once the patient has been extubated and is stable and after a bedside swallowing evaluation by an SLP. All patients are encouraged to advance their oral diet with the guidance of an SLP and work toward maintaining all nutrition by mouth. Postoperative dysphagia is common. It is sometimes necessary to discharge patients from the hospital with an NG tube if oral intake remains inadequate, although almost all patients will regain meaningful swallowing within 2 weeks. For open surgical resection, the postoperative course is variable. For patients undergoing larger resection or salvage resection, a gastrostomy tube may be considered if long-term

C

E

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dysphagia is predicted. Otherwise, NG tube placement is necessary for enteral feeding. In non-irradiated patients, oral intake may be initiated at postoperative day 5–7 if internal and external wounds are healing well. In the salvage setting, our preference is to wait 2–3 weeks before initiation of oral intake. This should also be done with the assistance and guidance of an SLP. If pharyngeal leak is suspected, a Gastrografin video swallow study may be useful, although most pharyngocutaneous fistulas are obvious on clinical evaluation. Regarding tracheostomy management, most patients can be decannulated before hospital discharge. The tube cuff is deflated by postoperative day 2–3 when the patient can manage and

D

F • Fig. 33.19, cont’d  C, Surveillance PET-CT 1 year after chemoradiation, demonstrating local recurrence in the base of tongue. D, Incision design for salvage oropharyngectomy via lip-splitting approach. E, Incision design, intraoperative view. F, Paramedian stepped mandibulotomy. Continued

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G

H • Fig. 33.19, cont’d  G, Mandibulotomy and swing exposing the latero-posterior oropharynx and base of tongue to facilitate resection. H, Oropharyngectomy, intraoperative view.

swallow his or her own secretions. Patients should be explicitly instructed to practice swallowing saliva and use maneuvers demonstrated by the SLP. Between postoperative days 4 and 5, tracheostomy can be downsized in preparation for decannulation. Our preference is to use Jackson metal tracheostomy tubes with a 2-mm internal diameter drop from the previous tube. The outer diameter of Jackson tubes are lower profile and smooth and less irritating to the tracheal mucosa. This is helpful in reducing tracheal secretions and discomfort. The decreased bulk is also less obtrusive to swallowing mechanisms. A capping trial follows, and if the patient can remain plugged for 24 hours (including overnight), decannulation is appropriate.

Reconstruction The primary goal of reconstruction of the oropharynx is to provide coverage and protect vital structures. More specifically, it is to protect the carotid artery and prevent salivary leakage into the danger space (if the tumor requires a resection deeper than the retropharyngeal space). A secondary goal is to preserve function. The muscles of the base of tongue, lateral pharyngeal walls, posterior pharyngeal wall, and soft palate are critically important for both speech and the oral and oropharyngeal phases of swallowing. These two goals create unique challenges. To understand these properly, it is helpful to review the anatomy.

Functional Anatomy The base of tongue is composed of extrinsic tongue muscles (hyoglossus, genioglossus, styloglossus, and palatoglossus) as well as the intrinsic tongue muscles. It is essential for both the oral and oropharyngeal phases of swallowing. In the oral phase, the base of tongue creates a seal with the soft palate and posterior pharyngeal wall, preventing early passage of the food into the

oropharynx and subsequent aspiration. The base of tongue then works to propel the food distally during the oropharyngeal phase. The lateral pharyngeal walls, which include the tonsillar fossae, is composed of (from superficial to deep) mucosa, pharyngobasilar fascia, superior pharyngeal constrictor muscle, buccopharyngeal fascia, and the parapharyngeal space. The palatoglossus, palatopharyngeus, and stylopharyngeus muscles are intertwined with the superior pharyngeal constrictor muscles. Deep to the parapharyngeal space is the carotid sheath and its contents. The posterior pharyngeal wall, from superficial to deep, is composed of mucosa, pharyngobasilar fascia, superior and middle pharyngeal constrictor muscles, buccopharyngeal fascia, retropharyngeal space, alar fascia, the danger space, prevertebral fascia, and prevertebral muscles. The soft palate is composed of the tensor veli palatini, levator veli palatini, musculus uvulae, palatoglossus, and palatopharyngeus. The lateral pharyngeal walls and posterior pharyngeal wall function to constrict the diameter of the oropharynx. The soft palate muscles elevate and lengthen the palate, pushing posteriorly against the narrowed oropharyngeal lumen, creating velar closure for speech and preventing nasal regurgitation of food during swallowing. The same narrowed oropharynx comes into contact with the elevated base of tongue during the oral and oropharyngeal phases of swallowing.

Defect Analysis T1/T2 tumors treated with primary TORS rarely require reconstructive surgery because they heal well with secondary intention. Despite healing with scarring that results in less dynamic movement and altered form, the remaining unoperated areas can often compensate, with a notable exception. Even small tumors that extend onto and include the posterior free edge of the soft palate may necessitate some form

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

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I

J

K

L • Fig. 33.19, cont’d  I, Resection specimen. J, Inset of the radial forearm free flap and microvascular anastomosis. K, Intraoperative view before mandibular osteosynthesis with superior and inferior border plates and screws. L, Postoperative appearance of patient 6 months after salvage surgery.

of reconstructive surgery to avoid postoperative velopharyngeal insufficiency. In the postradiation salvage setting, defects of the lateral pharyngeal wall should not be left to heal by secondary intention, because the hypocellularity and hypovascularity of the tissue bed are unreliable. Wound infection in this area has the potential for catastrophic carotid artery compromise. Open surgical resection via mandibulotomy approaches or lateral pharyngotomy also generally require free flap reconstruction.

Planning of Reconstructive Surgery The armamentarium for oropharyngeal reconstruction involves using primary closure when possible, local flaps (pharyngeal flaps), free tissue flaps (radial forearm flaps and anterolateral thigh flaps are the most commonly employed by authors Patel, Cheng, and Bell), regional flaps (pectoralis major flap), or a combination of these. The type of flap depends on the nature of the defect.

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Successful reconstruction of base of tongue defects depends on the amount of remaining mobile tongue and the preservation of the lingual and hypoglossal nerves (at least on one side). If half of the base of tongue remains, function is often well preserved. However with near total or total base of tongue resections, restoring function relies on the mobility of the soft palate and pharyngeal walls. To facilitate this, it is necessary to use a flap of sufficient bulk to create a base of tongue mound. This can be done with either an anterolateral thigh flap or a radial forearm flap. A modification of the forearm flap includes a subcutaneous proximal extension (in the shape of a beaver tail) that can be folded under to increase the bulk of the tongue posteriorly.

Surgical Complications Surgical complications are not uncommon in head and neck oncology, given the complex anatomy, violation of sterile and unsterile body compartments, neurovascular density of the head and neck, and critical functional elements of the affected organs. With improved surgical techniques, antibiotics, and routine use of vascularized flaps, major complications directly related to surgery have decreased substantially. As survivorship improves, particularly in the era of HPV-related oropharyngeal cancer, long-term complications are more evident. The importance of post-treatment quality of life has been studied extensively, and although advances in medicine and surgery have not made a major impact on OS, functional preservation has improved dramatically. Pharyngocutaneous fistula, dental injury, dehydration, dysphagia, airway edema, malocclusion, nerve injury, and bleeding are associated with surgical approaches to the base of tongue.* Intraoperative hemorrhage and nerve damage are perhaps the two most important complications related to surgical extirpation of base of tongue tumors. The hypoglossal nerve and external carotid system, particularly the lingual artery, are most at risk. Although the overall rates of intraoperative hemorrhage and iatrogenic nerve injury are low, postoperative bleeding is the most common worrisome complication after modern surgery for base of tongue neoplasms, occurring in up to 10% of patients undergoing TORS.26,50,52 In a recent retrospective single-institution analysis of 224 consecutive patients undergoing TORS, postoperative hemorrhage occurred in 10% of patients ranging from postoperative day 1 to 42. Of patients with postoperative bleeding, 82% required surgical. intervention for hemorrhage control, with a mortality rate of 0.9%.26 Many long-term complications are associated with adjuvant therapy, including xerostomia, dental disease, osteoradionecrosis, dysphagia, and radiation-induced fibrosis. Long-term surgical complications of surgery for early-stage base of tongue cancer are primary related to dysphagia and aspiration, although with modern minimally invasive techniques and sophisticated vascularized reconstruction, they are managed well. The rates of permanent gastrostomy tube dependence and tracheostomy dependence are low when compared with patients undergoing primary chemoradiotherapy or patients undergoing therapy for advanced-stage oropharyngeal cancer.25,28,51,53 * References: 25, 26, 41, 42, 45, 46, 50, 51.

Post-treatment Surveillance All head and neck cancer patients require structured surveillance and follow-up because treatment failure and recurrence rates approach 40–50% across all stages. Disease control and cure rates are excellent for early-stage base of tongue cancer, particularly HPV-related disease; salvage in recurrent disease may be better if the recurrence is identified early. Controversy exists among oncologists regarding the optimal surveillance schedule and diagnostic tests. Beyond a 12-week post-treatment PET-CT, the NCCN does not endorse any particular imaging studies. Current NCCN guidelines recommend structured follow-up and examination that decrease in frequency over a 5-year period. There is scant evidence that imaging surveillance can improve survival outcomes; however, several studies have suggested that more intensive follow regimens do not lead to improved survival in oropharyngeal carcinoma.54 Two negative PET-CT scans within the first year of treatment may have an implication on prognosis, and PET-CT appears to be the most sensitive imaging study to detect recurrence, but there is a dearth of high-level evidence that endorses the routine use of PET-CT or other imaging studies on a routine basis during a typical 3- to 5-year follow-up period.54,55 A recent European retrospective analysis of 146 patients with advanced oropharyngeal cancer treated with definitive chemoradiation demonstrated overall sensitivity and specificity of 12-week post-treatment PET-CT of 92% and 85%, respectively; however, the 3-year PFS rates for patients with reassuring PET-CT results were 91.7% for HPV-positive patients and 66.2% for HPV-negative patients.56 These rates are similar to previously published 3-year diseasefree survival rates for these groups of patients, suggesting that negative post-treatment PET-CT scans have little implication for survival. In 2016, the PET-NECK Trial Management Group published the results of a prospective randomized clinical trial of 564 patients with N2 or greater head and neck cancer undergoing definitive chemoradiotherapy followed by either 12-week post-treatment PET-CT with or without neck dissection or 12-week post-treatment planned neck dissection to assess the non-inferiority of PET-CT. Of the patients enrolled, 84% were treated for oropharyngeal cancer. The data demonstrated that the 2-year OS rate was similar between groups—84.9% in the surveillance group and 81.5% in the planned neck dissection group, with the hazard ratio for death slightly favoring the PET-CT–guided surveillance group. There was no significant difference between the groups with respect to p16 expression (75% of oropharyngeal cancers treated in the study). PETCT–guided surveillance resulted in savings of approximately $2190 in U.S. dollars per person over the duration of the trial. This established non-inferiority and cost-effectiveness of PETCT–guided post-treatment surveillance over planned neck dissection.55 At our institution, patients are seen every 3 months for the first 2 years after completion of treatment, then every 4 months during the third year, every 6 months for the fourth year, and once in the fifth year. Follow-up examination includes a

CHAPTER 33  Early HPV-Related Base of Tongue Cancer

comprehensive review of systems and head and neck physical examination. All patients with base of tongue cancer undergo recorded high-definition fiber-optic examination at each visit. Tobacco cessation counseling and risk reduction counseling are provided to appropriate patients, and the warning signs of recurrence are reviewed (new-onset or worsening pain, dysphagia, otalgia, odynophagia, dysphonia, dysarthria, weight loss, malaise).

Speech and Swallowing Therapy Dysphagia is a common deficit during and after the treatment of base of tongue cancer. It can occur after surgery, chemotherapy, RT, or a combination of any of the three. Dysphagia has an impact on nutrition, hydration, wound healing, and possible aspiration pneumonia. Surgical resection of base of tongue tumors can modify the structures used to transfer the bolus and protect the airway and nasopharynx. Surgery can reduce velar closure, which may allow foods or liquids to leak into the nasal cavity, and also changes the vocal resonance when speaking. It can reduce the base of tongue–posterior pharyngeal wall contact during swallowing, resulting in post-swallow pharyngeal residue, premature spillage of the bolus, delayed initiation of the swallow, and reduced hyolaryngeal elevation. These can result in aspiration before or after the swallow. RT, with or without chemotherapy, has acute and long-term effects on swallowing. Acutely, the treatment sequelae have a significant impact on swallowing and speech. These include xerostomia, mucositis, odynophagia, neutropenia, nausea, and malaise. Patients should be monitored closely through radiation for swallowing function, and diet texture tolerance. After completion of radiation, the patient may have long-term dysphagia secondary to radiation fibrotic effects, taste changes, xerostomia, odynophagia, and trismus.

Pretreatment Evaluation Before treatment of the cancer, an SLP should evaluate the patient’s current swallowing and speech abilities. Pretreatment swallowing evaluations allow for assessment of patient’s nutritional intake and anatomic and physiologic changes. A thorough oral-motor examination is completed to assess range of motion, strength, and coordination of the oral-pharyngeal system. A clinical swallowing evaluation is used to examine bolus manipulation and control, transfer, weakness, residue, and hyolaryngeal elevation and excursion, and to allow for determination of aspiration risk. Occasionally, an imaging procedure is used to fully visualize the physiology of the swallow. Most often this is done with either a modified barium swallow (MBS) study or a fiber-optic endoscopic evaluation of swallowing (FEES). Counseling before treatment will focus on potential for changes in speech and swallowing after surgery or during and after chemoradiation. If needed, swallowing compensatory strategies may be introduced, and oral supplements or possibly early alternative nutrition may be indicated. This allows for improved nutritional reserves before the beginning

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of treatment. Patients who have dysphagia before treatment are at higher risk of long-term dysphagia and possibly permanent tube feeding.57

Postsurgical Speech and Swallowing Evaluation After completion of surgery, the patient’s dysphagia should be reevaluated. Severity of the patient’s dysphagia is related to the size of the surgical resection, type of surgical reconstruction, and decreased sensation postoperatively. Postoperative swelling and pain will also have a significant impact. Surgical resection involving the pharyngeal wall and/or the base of tongue will have increased impact on swallowing. Tonsil resection surgery can affect the bolus transfer into the pharynx, velar closure, and base of tongue contact with the posterior pharyngeal wall. This will often result in delayed oral transit, pharyngeal residue, vallecular pooling, premature spillage of the bolus, and incomplete laryngeal closure. An instrumental swallowing evaluation is often completed to visualize the physiology of the swallow mechanism. Treatment for swallowing difficulties may include postural changes, diet texture changes, and compensatory strategies. As postoperative swelling reduces, swallowing should improve, although it may continue to be impaired. Introduction of range-of-motion and strengthening exercises has been shown to improve swallow safety.58

Speech and Swallowing Evaluation After Chemoradiation Therapy Swallowing should be monitored before, during, and after chemoradiation therapy. Effects of radiation, with or without chemotherapy, result in changes to the swallowing structures and function, taste, and mucosal lining and the presence of pain. For radiation directed at the base of tongue or tonsil, there can be changes to the motility of the structures including reduced jaw opening, reduced base of tongue retraction, reduced velopharyngeal closure, reduced laryngeal elevation, impaired pharyngeal constriction, and delayed laryngeal vestibule closure. Sequelae related to chemoradiation also affect swallowing, including xerostomia, reduced saliva, and mucositis. Swallowing disorders occur during treatment and can persist long term. There can be continued deterioration of swallowing function years after chemoradiation, secondary to fibrosis. Treatment strategies during chemoradiation usually involve range-of-motion and strengthening exercises, diet texture changes, and compensatory strategies.

Swallowing Exercises Swallowing exercises can be beneficial in treating dysphagia secondary to oropharyngeal cancer. These exercises can help to strengthen swallowing structures, improve bolus control, and improve airway protection. For example, the tongue hold swallowing exercise59 is designed to improve base of tongue and pharyngeal strength. The patient holds the tip of the tongue

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gently between the front teeth, and maintains the posture while swallowing. This exercise causes the glossopharyngeal portion of the superior constrictor muscle to use more force in contracting. The Mendelsohn maneuver60 can be of benefit to maximize hyolaryngeal elevation. The patient holds the larynx up at the highest point for an extended time, then completes the swallow. The goal is to increase the extent and duration of the laryngeal elevation. The breath hold58 strategy is used to maximize full closure of the laryngeal vestibule. The patient takes a breath, bears down, and holds the breath for an extended time, then repeats the exercise. There is significant variability with regard to swallowing deficits for patients with tonsil cancer. Early evaluation of swallowing and introduction of swallowing strategies are beneficial to maintain safe oral intake.

Dental Management Dental and Oral Considerations Patients diagnosed with T1/T2 base of tongue SCC present a particular management challenge for the dental and oral oncologist. Because as many as 75% of head and neck cancer patients, with any primary location or stage of disease, have been reported to have foci of dental infection at the time of diagnosis, timely pretreatment dental and oral evaluation is essential.61 This increase in the likelihood of tooth damage is in theory due to a combination of direct damage to tooth structures and salivary dysfunction. The entire oral cavity must be considered as a potential focus for local and systemic complications for patients treated with RT and chemotherapy. Short-term risks are increased because these patients are likely to receive concurrent chemotherapy and because chronic dental infections may become acute during therapy, which alters or suppresses the immune response. These foci should be eliminated or treated before initiation of treatment, often at the time of staging laryngoscopy (if patients are being treated with definitive chemoradiation) or at the time of surgical resection before adjuvant therapy. Long-term complications from high doses of radiation to tooth-bearing areas of both the maxilla and mandible place the patient at risk for radiation caries, periodontal disease, dental pathology, and osteoradionecrosis. The larger volume of irradiated oral tissues increases the risk of oral discomfort from mucosal damage, salivary hypofunction and xerostomia, fibrosis of soft tissues, and secondary infections.62,63 Although there is limited evidence regarding standard radiation doses to tooth-bearing areas, these investigations call attention to the need for a comprehensive examination by a provider with specific training and knowledge in oncologic dentistry and oral care.

Future Directions The landscape of oropharyngeal cancer has evolved dramatically over the last decade. With the promise of immunotherapy and gene therapy for head and neck cancer, as well as minimally

invasive surgery and treatment de-escalation, we may see a paradigm shift toward personalized treatment and improvement in quality of life in the HPV era. The focus of treating patients in a multidisciplinary setting with an expanding library of clinical trials is conducive to comprehensive treatment of cancer patients and advancing the science of head and neck oncology.

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60. Lazarus C, Logemann JA, Gibbons P. Effects of maneuvers on swallowing function in a dysphagic oral cancer patient. Head Neck. 1993;15:419–424. 61. Walker MP, Wichman B, Cheng AL, et al. Impact of radiotherapy dose on dentition breakdown in head and neck cancer patients. Pract Radiat Oncol. 2011;1:142–148. 62. Hansen HJ, Maritim B, Bohle Iii GC, et  al. Dosimetric distribution to the tooth-bearing regions of the mandible following intensity-modulated radiation therapy for base of tongue cancer. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114: e50–e54. 63. Morais-Faria K, Menegussi G, Vasconcelos K, et al. Dosimetric distribution to the teeth of patients with head and neck cancer who underwent radiotherapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015;120:416–419.