Imaging of squamous cell carcinoma of the hypopharynx

Imaging of Squamous Cell Carcinoma of the Hypopharynx Frank A. Pameijer, Suresh K. Mukherji, AIfons J.M. Balm, and Bernard EA.M. van der Laan The hypopharynx is a clinically silent area and early lesions may be asymptomatic for a long period. At presentation, primary squamous cell carcinoma of this area is usually advanced. Almost all of these lesions are studied with imaging as part of the clinical work-up. The goal of this article is to help the practicing radiologist convey a report which provides information that will directly influence treatment of patients with hypopharyngeal carcinoma.

Copyright© 1998by W.B. Saunders Company

HE HYPOPHARYNX is situated below the 0ropharynx and cranial to the cervical esophagus (Fig 1). This makes it part of the gastrointestinal tract, rather than the larynx and respiratory tract. Tumors originating from the hypopharynx usually behave more aggressively than laryngeal tumors. They tend to infiltrate much more widely and are often found to be anaplastic in their histology. 1 In the spatial approach to neck anatomy, the hypopharynx, like the oropharynx and nasopharynx, is part of the pharyngeal mucosal (visceral) space. 2 More than 95% of malignant tumors occuring in this area are squamous cell carcinoma (SCC)) SCC of the hypopharynx is more common in men. Risk factors include tobacco and alcohol abuse. 4 In this paper the following topics will be discussed: (1) anatomy of the hypopharynx, (2) strategies for computed tomography (CT) and magnetic resonance imaging (MRI) of this region, (3) the impact of imaging in the treatment and management of patients with hypopharyngeal carcinoma, and (4) post-treatment evaluation

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ANATOMY OF THE HYPOPHARYNX

The hypopharynx (Latin: hypo = lower) is the most caudal portion of the pharynx that extends superiorly from the level of the hyoid bone to the caudal part of the cricoid, inferiorly (Fig 1). 3 Above

From the Departments of Radiology and OtolaryngologyHead and Neck Surgery, The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; the Departments of Radiology and Surgery, The University of North Carolina~School of Medicine, Chapel Hill, NC," and the Department of Otorhinolaryngology-Head and Neck Surgery, University Hospital Groningen, Groningen, The Netherlands. Address reprint requests to Frank A. Pameijer, MD, Department of Radiology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam. Copyright © 1998 by W.B. Saunders Company 0887-2171/98/1906-000558.00/0 476

the hyoid is the oropharynx. Below the cricoid cartilage, the hypopharynx becomes the cervical esophagus: Anatomically, the hypopharynx can be divided in three subsites: the (paired) pyriform sinuses, the posterior hypopharyngeal wall, and the postcricoid region (Figs 1,2). 3,6 Hypopharyngeal cancer arises most frequently in the pyriform sinus, comprising 65% to 75% of reported cases. 7 The hypopharynx and larynx are anatomically and functionally intimately related. This close association is important both from a clinical, as well as from an imaging standpoint. Partial surgical resection of hypopharyngeal carcinoma is exceptional, and surgical removal of these tumors almost always involves simultaneous surgery of the larynx. To create safe margins, it is sometimes necessary to remove a normal functioning larynx. Because of this intimate anatomic and functional relationship, imaging studies of the hypopharynx must always include the larynx.

Pyriform Sinus "Pyriform" is derived from the Latin "pirum" or "pear." This anatomic description is used to describe the two pear-shaped grooves of the hypopharynx that are created by the impression of the larynx into the anterior aspect of the pharynx (Fig 2). 8 This creates pharyngeal grooves posterolateral to the larynx. A frontal view of a barium study will often show these as two symmetric stalactite-like structures (Fig 3). Each pyriform sinus is made up of a medial, an anterior, and a lateral wall (Fig 4). The medial wall is the free edge of the aryepiglottic fold (AE-fold), separating the pyriform sinus from the larynx. It is important to realize that the AE-fold "plays on two teams." Its anterior surface is endolarygeal and is part of the supraglottic larynx. At the same time, its posterior surface forms the medial wall of the pyriform sinus and is a part of the hypopharynx. The anterior wall of the pyriform sinus is in direct

Seminars in Ultrasound, CT, and MRI, Vo119, No 6 (December), 1998: pp 476-491

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Fig 1. Anatomy of the hypopharynx. Diagram of the hypopharynx. The heavy black lines indicate the region of the hypopharynx. (Reprinted with permission.2e)

Hyoid Thyrohyoid membraneS Epiglottis Aryepiglottic folds t ' " Thyroid cartilage f l Pyriform sinuses'" Arytenoid cartilage" Cricoid cartilage "I Post-cricoid reaion Posterior wall

contact with the posterior paralaryngeal space. The lateral wall is formed superiorly by the thyrohyoid membrane (membranous pyriform sinus) and inferiorly by the thyroid cartilage (cartilagenous pyriform sinus). 6 The posterior wall of the pyriform sinus is anatomically not defined, because this area is in direct continuity with the posterior pharyngeal wall (Fig 4B). Therefore, if a pyriform sinus tumor extends onto the posterior wall, this should be reported as involvement of a second subsite (ie, posterior pharyngeal wall). According to current TNM criteria (Table 1), this would upstage a clinical T1 lesion to T2. 9,]° The upper limit of the pyriform sinus is the pharyngoepiglottic fold (Fig 2). The lowermost boundary of the pyriform sinus, called the apex, lies at the level of the true vocal cord. The apex is well-visualized on the frontal view of a barium study (Fig 3). On cross-sectional images, the apex is located at the level of the cricoarytenoid joint (Figs 2, 5).

Posterior Hypopharyngeal (Pharyngeal) Wall The posterior wall of the hypopharynx, which is 4 to 5 cm wide and 6 to 7 cm high, starts at the level of the valleculae.6 Above this, the posterior wall is continuous with the posterior wall of the oropharynx. Caudally, the posterior wall merges with the mucosa covering the cricopharyngeus muscle and then with the cervical esophagus (Fig 1). The entire thickness of the posterior hypopharyngeal wall from the surface of the mucosa to the vertebral body is no more than 1 cm (Fig 2). 3

Postcricoid Area The postcricoid area, also called the pharyngoesophageal junction, extends from the level of the arytenoid cartilages to the inferior border of the cricoid cartilage2 It is composed of the mucosa covering the posterior aspect (lamina) of the cricoid cartilage (Fig 2). This area is the interface between the hypopharynx posteriorly and the larynx anteri-

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Fig 2. Pyriform sinus carcinoma. Schematic illustrations demonstrate potential pathways of spread for a pyriform sinus carcinoma (black arrows). (A) Transverse illustration at the level of the cricoarytenoid joint; A, arytenoid cartilage, c, cricoid cartilage. The pharyngeal contrictor muscle fibers insert on the posterolateral aspect of the thyroid cartilage 1 cm anterior to the posterior cartilage border (black arrowhead). (B) Longitudinal illustration. The hypopharynx is seen from the dorsal side (posterior pharyngeal wall has been cut in the midline and retracted laterally). Hypopharyngeal subsites: Pyriform sinus (1), postcricoid area (2}, posterior hypopharyngeal wall (3), pharyngoepiglottic fold (arrowhead). (Reprinted with permission from Mukherji SK, et al: Imaging squamous cell carcinomas of the upper aerodigestive tract: what clinicians need to know. Radiology 205:629-646, 1997J s)

orly, sometimes referred to as the "party wall. ''3 Directly caudal to this, the esophageal verge, or esophageal inlet, is found. This is the junction between the postcricoid portion of the hypopharynx and the cervical esophagus. At this junction, the inferior pharyngeal constrictor fibers merge with the circular muscles of the upper cervical esophagus. It can be observed on endoscopy, but also on cross-sectional imaging by noticing the flat ellipsoid shape (Fig 6), as opposed to the cervical esophagus, which has a rounded appearance.

Muscles, Nerves, Blood Vessels and Lymphatics Beneath the mucosa, the hypopharyngeal mucosal space consists only of the inferior pharyngeal constrictor muscle and its neural and vascular supply and profuse capillary lymphatics. The inferior pharyngeal constrictor muscle fibers arise from a posterior midline raphe and insert on

the posterolateral aspect of the thyroid cartilage 1 cm anterior to the posterior cartilage border (Fig 2). The lowermost portion of the inferior pharyngeal constrictor, the cricopharyngeus muscle or superior esophageal sphincter, is composed of nonraphed fibers that arise in a circular fashion from either side of the cricoid cartilage. These fibers merge inferiorly with the circular muscles of the cervical esophagus, ie, the esophageal verge (Fig 6).11 Motor innervation to the inferior pharyngeal constrictor muscle is supplied by the pharyngeal plexus, which are branches of the vagus nerve. Sensory information from the hypopharynx travels along the glossopharyngeal nerve and the internal laryngeal branch of the superior laryngeal nerve, which arises from the vagus. 3 The internal branch of the superior laryngeal nerve is located in the anterior wall of the pyriform sinus at the junction of its middle and lower third. Perineural invasion of

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usually advanced (ie, stage T3-T4). 13-16 This tendency for tumors of the hypopharynx to be advanced partly accounts for the fact that up to 75% of patients have clinically positive neck nodes on admissionP However, a discrepancy between a small primary lesion and large regional metastasis is not infrequently observed. Eventually, 20% to 40% of patients will also develop distant metastases, occurring preferentially in the lungs. 17,18 In

Fig 3. Normal hypopharynx. Frontal (AP) view of a barium study, air-contrast Barium coats the pyriform sinuses (small arrows). Apex (large arrows) well-visualized on both sides,

this branch can account for otalgia (referred pain to the external auditory canal by way of the auricular branch of the vagus nerve). Because this is sometimes the only presenting nonspecific complaint, this may develop as a treacherous symptom. 5 Branches of the superior and inferior thyroid arteries and veins supply most of the hypopharynx.ll The lymphatic drainage of the hypopharynx is profuse and may explain the often dramatic early lymphatic spread of this disease. The primary echelon lymph nodes are the upper and mid-jugular nodes (levels II and III); less frequently, the posterior cervical nodes (level V) are involved. 3 Extension of the tumor to the posterior wall of the hypopharynx places the retropharyngeal nodes at risk. 6A postcricoid primary may jeopardize the mid and lower jugular nodes (levels III and IV), as well as the paratracheal nodes (level V]). 12 CLINICAL PRESENTATION

The hypopharynx is a clinically "silent" area, and early lesions may be asymptomatic for a long period. At presentation, primary SCC of this area is

Fig 4. Axial CT anatomy of the hypopharynx. (A) CT section at the level of the mid-pyriform sinus during quiet respiration, The medial wall (white arrowhead) consists of the aryepiglottic fold which separates the larynx (anteromedially) from the hypopharynx (posterolaterally). The anterior wall (small white arrow) is in direct contact with the fat in the posterior paralaryngeal space. The lateral wall (large white arrow) is in direct contact with the thyroid cartilage. (B) CT section at the same level as in (A). Distention of the (normal) pyriform sinuses during Valsalva maneuver. The aryepiglottic folds are pressed together and move anteriorly which demonstrates the full extent of the posterior hypopharyngeal wall,

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PAMEIJER ET AL Table 1. T-Staging: Hypopharynx

Tis carcinoma in situ T1 Tumor limited to one subsite * of hypopharynx and 2 cm or less in greatest dimension T2 Tumor involves more than one subsite of hypopharynx or an adjacent site, or measures more than 2 cm but not more than 4 cm in greatest dimension, withoutfixation of hemilarynx T3 Tumor measures more than 4 cm in greatest dimension, or with fixation of hemilarynx T4 Tumor invades adjacent structures (eg, thyroid/cricoid cartilage, carotid artery, soft tissues of neck, prevertebral musculature, thyroid, and/or esophagus) *Hypopharyngeal subsites are the pyriform sinus, postcricold area (pharyngoesophageal junction), and posterior pharyngeal wall.

addition, around 10% of patients with SCC of the hypopharynx have a synchronous or metachronous second primary tumor of the upper respiratory or digestive tract, i9.20

Fig 6. Clinically unsuspected involvement of the esophageal verge owing to carcinoma of the right pyriform sinus (not shown). (A) CT section at the level of the low postcricoidesophageal verge region shows asymmetric thickening on the right side (arrowheads). No mucosal lesion was observed at this level. Note enhancement of the mucosa of the collapsed esophageal inlet (curved arrow). (B) T2-weighted MR section at the same level confirms submucosal invasion of the esophageal verge. Imaging findings allowed for anticipation of gastic pull-up for pharyngeal reconstruction.

Fig 5. T1 pyriform sinus carcinoma. CT images of a 4.6 cm 3 squamous cell carcinoma which was successfully controlled with definitive RT. (A) There is an exophytic lesion (arrows) involving the medial wall of the right mid-pyriform sinus. (B) At the level of the pyriform sinus apex {small arrow), no tumor is observed. The appearance is similar to the opposite apex (large arrow). A, arytenoid cartilage). (Reprinted with permission. 40)

When symptomatic, the hallmark of hypopharyngeal wall and pyriform sinus cancer is sore throat (odynophagia). 3 Advanced lesions produce a characteristic triad of odynophagia, referred otalgia, and dysphagia. 7 Blood-streaked saliva, owing to tumor ulceration, and voice change are late symptoms. Frequently, patients are first observed with an asymptomatic neck mass as the only presenting symptom. Most patients are first observed in the outpatient clinic, where initial staging is performed by the otolaryngologist using indirect laryngoscopy and neck palpation. Both the American Joint Committee on Cancer as well as the International Union against Cancer TNM staging systems are used widely.9,10The criteria for T-staging of hypopharyngeal cancer are identical for both staging systems (Table 1).

IMAGING OF HYPOPHARYNGEAL CANCER

Small lesions of the pyriform sinus are easily missed. Lesions of the apex of the pyriform sinus and postcricoid area are not visible by indirect laryngoscopy and produce indirect findings such as pooling of secretions in the pyriform sinus and arytenoid area, indicating (partial) obstruction of the upper cervical esophagus. Edema of the arytenoids and asymmetry of the pyriform sinuses are clues to postcricoid or low-lying pyriform sinus tumors. 3 It may be impossible to evaluate the status of the apex endoscopically because of mechanical obstruction by lesions arising in the upper- or mid-pyriform sinus. This area is well-appreciated both on CT (Fig 7A), as well as on MRI (Fig 7B). Cross-sectional imaging may show positive retropharyngeal nodes that are difficult to detect clinically (Fig 8). These nodes are not accessible to palpation and therefore are often clinically occult. Ballantyne, who first drew attention to these nodes, reported an 44% incidence of positive retropharyngeal nodes in moderately advanced carcinoma of the pharyngeal wall and pyriform sinus treated by surgery. 2~ The extent of disease may be underestimated at endoscopy owing to the tendency of hypopharyngeal carcinomas to extend beneath the mucosal surface. On imaging, submucosal extension can frequently be visualized or suspected, which contributes to a more correct staging of the disease. Recent investigations have shown for laryngeal carcinoma that the combination of clinical/endoscopic evaluation and imaging, either CT or MRI, resulted in significantly improved pretherapeufic staging accuracy (80% v s 87.5%) versus 55% for clinical/ endoscopic evaluation alone. 22 The imaging techniques for the hypopharynx and larynx are identical owing to the close anatomic relation. 3 Thus, in addition to ENT-mirror examination and endoscopy under general anesthesia, the work-up for staging of hypopharyngeal malignancies should include cross-sectional imaging (CT or MRI), for accurate tumor mapping, as well as nodal staging. The imaging study should preferentially be performed before biopsy. Chest roentgenography is performed on a routine basis to screen for lung metastases or a second primary tumor. In many centers, ultrasound-guided fine needle aspiration cytology (USFNAC) has become part of the staging procedure.

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Fig 7. T4 pyriform sinus carcinoma. (A) CT section at the level of the cricoarytenoid joint shows obvious tumor in the left pyriform sinus apex. The left lamina of the thyroid cartilage, as well as the left arytenoid cartilage, are sclerotic; suspicious for cartilage invasion. Posteriorly, there is erosion of the cartilage adjacent to tumor (arrow). At the external surface of the thyroid, similar erosions are located (curved arrows) at the attachment of the constrictor muscle fibers, suspicious for extralaryngeal spread. (B) Tl-weighted fatsuppressed contrast-enhanced MR section at the same level shows enhancement of tumor in the pyriform sinus apex as well as extralaryngeal "wraparound" tumor growth (arrowheads). Note enhancement of the medullary space of the left thyroid lamina, suspicious for cartilage invasion and/or reactive inflammation (curved arrow).

IMAGING OF THE HYPOPHARYNX

A variety of conventional methods have been applied to evaluate hypopharyngeal tumors, including soft tissue views of the neck, xeroradiography, plain film tomography, laryngography, and barium swallow. All of these studies have been replaced by CT and MRI, which should be done before biopsy. 3 Occasionally, a mucosal abnormality of the hypopharynx is first detected on a barium swallow, ordered for the evaluation of dysphagia or odynophagia. Although a barium swallow accurately

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invasion or submucosal spread toward the esophageal verge). We cannot supply the "ideal" imaging protocol, because available imaging resources and local experience may vary. However, we will outline the (minimal) requirements for a diagnostic study. Irrespective of the equipment used (CT slice-toslice, spiral CT, or MRI), there are a few technical details regarding positioning of the patient and scan angulation that are absolutely essential. The images are obtained with the patient supine and with quiet respiration. The neck should always be slightly hyperextended so that the hypopharynx is drawn higher in the neck to help avoid artifacts produced by the shoulders. The head is carefully aligned in the cephalocaudal axis, to make it possible to compare symmetric structures (eg, the pyriform sinuses). Malposition may result in appearance that simulates disease or asymmetry.

CT

Fig 8. Retropharyngeal node metastasis. (A) CT section at the Cl/C2 level shows a right retropharyngeal node with irregular enhancement (arrows). (B) The CT examination was repeated after 2 months. Section at the same level shows extensive growth of the lymph node, which has become fully necrotic.

displays the mucosal disease, it is never sufficient for staging, because deep extension is not shown. Pretreatment imaging, either CT or MRI, has become essential for the correct pretherapeutic staging and proper treatment of laryngopharyngeal tumors. 13In this era of cost concern, it seems to be a good principle to do one cross-sectional study that accurately stages the disease for the lowest price. Personally, we follow the approach advocated by Mancuso et al.3,14For hypopharyngeal tumors, they prefer CT as a first choice. In approximately 10% of cases, an additional MRI study is needed to resolve specific issues that would have consequences for treatment (eg, prevertebral muscle

Contiguous sections should be obtained through the primary site, whereas an intersection gap of 2 mm can be used to image the remainder of the neck. 15 The maximal section thickness should not exceed 3 ram. The field-of-view (FOV) must be magnified to optimize spatial resolution. The optimal F O ¥ varies between 14 and 18 cm, depending on the size of the patient. Intravenous (non-ionic) contrast medium is used for all studies performed to evaluate neoplasms. This increases the conspicuity of the primary tumor and is essential for evaluating the neck nodes. Pre-scanning bolus administration followed by drip infusion is the preferred method. In addition to the soft-tissue window settings, the images of the laryngeal framework should be reconstructed with bone algorithms, which are helpful for detection of bone and cartilage invasion. In the evaluation of a hypopharyngeal malignancy, especially when the posterior pharyngeal wall is involved, the C1-C3 region should be included routinely in the study for the evaluation of the retropharyngeal nodes. The scan should end at the level of the clavicles. Cranial of the alveolar ridge, the scan plane should be parallel to the hard palate. Caudally, the plane should be parallel to the true vocal cord (TVC), as described previously. 14 Additionally, this technique will minimize artifacts

IMAGING OF HYPOPHARYNGEAL CANCER

from dental amalgam, presuming that the two aquisitions overlap. If spiral/helical CT is available and the patient can hold his/her breath long enough, a single breath-hold, dynamic aquisition is possible. If such a spiral data set is acquired, reconstructions in the coronal plane can be made if there is uncertainty about the cranial-candal spread of tumor?

MR A neck surface coil should be used for evaluation of the hypopharynx. Careful instruction of the patient by the technologist, or supervising radiologist, is even more crucial than with CT because respiratory and/or swallowing artifacts may seriously degrade the MR study. Patients should be encouraged to use "abdominal," instead of "thoracic," respiration to minimize respiratory misregistration. The primary site should be studied in both the axial and coronal plane. When the tumor is located on, or extending to, the posterior pharyngeal wall a sagittal aquisition may be added. The ideal section thickness is 4 mm or less with interslice gap of 1 mm or less. The optimal FOV for the axial views is 16 to 18 cm for Tl-weighted sequences and 18 to 20 cm for T2-weighted sequences. This slightly larger FOV with the T2-weighted sequences results in a better signal-to-noise ratio. Becanse of inherent signal intensity differences between tumor, fat and muscle, accurate delineation of primary tumor extent is often possible using Tl-weighted images only. However, we use intravenous paramagnetic contrast material routinely for SCC of the hypopharynx because it often further increases the conspicuity of the primary tumor and is essential for the evaluation of the cervical nodes. We suggest that Tl-weighted images be obtained before and after injection of intravenous paramagnetic contrast material. The non-enhanced Tl-weighted sequence should be performed in the same plane before contrast material administration so high-signalintensity fat or proteinaceous fluid will not be confused with enhancement. We acquire the postcontrast images with fat-saturation, which permits better identification of the tumor margins because it helps separate the enhancing tumor margins from background fat.l 6

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PATTERNS OF TUMOR SPREAD IN HYPOPHARYNGEAL CANCER

Pyriform Sinus A small (T1) pyriform sinus tumor may he confined to one wall (Fig 5A). More commonly, pyriform sinus cancer will appear as a thick, infiltrating mass surrounding the pyriform sinus with involvement of all three walls (Fig 9). Spread of such a tumor to the posterior pharyngeal wall indicates involvement of more than one subsite of the hypopharynx and upstages the tumor to T2 (Fig 10). Endolaryngeal spread. Clinically inapparent submucosal spread to the endolarynx occurs when the tumor penetrates the anterior wall of the pyriform sinus and grows ventrally in the paraglottic space (Fig 9). This growth may extend to the preepiglottic space (PES) and onto the contralateral hernilarynx beneath intact mucosa. Alternatively, a pyriform sinus cancer may penetrate or spill over the aryepiglottic fold to reach the endolarynx. Apex involvement. The apex of the pyriform sinus is located at the level of the true vocal cord (TVC). A mass at this level or obliteration of the deep tissue (fat) planes is indicative of apex involvement. Careful comparison with the normal side is helpful to detect subtle disease (Fig 9). Anterior spread of tumor through the "thyroarytenoid" gap results in invasion of the paraglottic fat at this level (Fig 9). Medio-candal spread from the apex may extend toward the postcricoid region. Cartilage invasion (T4). The apex of the pyriform sinus is closely associated with the laryngeal cartilages (arytenoid, cricoid, and thyroid). Therefore, tumors that involve the apex are highly likely to invade the larynx and cause erosion and/or invasion of cartilage. Anterolateral spread results in invasion of the thyroid lamina (Fig 7). Direct anteromedial spread of these tumors results in invasion of the arytenoid and cricoarytenoid joint. Because of invasion of the deep musculature, the cord may become fixed (T3). Tumors located at the upper pyriform sinus frequently erode and/or invade the superior horn of the thyroid cartilage. Sclerosis of (ossified) laryngeal cartilage (arytenoid and/or cricoid) adjacent to, or in the vicinity of, the primary tumor is not infrequently observed (Figs 9, 10). On CT, this is observed as increased density owing to thickening of the cortex and/or

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Fig 9. T1 pyriform sinus carcinoma. CT study of a 9.4 cm 3 squamous cell carcinoma that was controlled at the primary site with RT, (A) At the mid-pyriform sinus level, there is involvement of the aryepiglottic fold and all three walls of the pyriform sinus, (B) At the level of the true vocal cords there is minimal (4 x 4mm) involvement of the pyriform sinus apex (small white arrow), with subtle obscuration of the deep tissue planes {compare to the normal left side). There is associated sclerosis of the right arytenoid cartilage (A). Also there is widening of the right thyro-arytenoid gap (curved white arrow) and obliteration of the ipsilateral paraglottic space, suggestive of endolaryngeal tumor spread {compare to normal left side), c, cricoid cartilage. {C) Post RT CT section at the same level as Fig 9A shows complete regression of the mass. Expected post RT findings include thickening of the platysma muscle (open arrow), reticulation of the subcutaneous and deep fat {arrowheads), symmetric thickening of the aryepiglottic folds and retropharyngeal space edema (curved arrows). Compare with (A) {pre RT). (Reprinted with permission.40)

increased density of the medullary space. The significance of this finding, ie, increased ossification, is currently not precisely understood. Previous studies have shown that sclerosis might be suggestive of microscopic tumor invasion.13,23 On the other hand, reactive inflammation, which is frequently observed in combination with these tumors, is also capable of inducing sclerosis without any tumor invasion. 13 Esophageal verge involvement (T4). Spread from the lower postcricoid region to the esophageal verge may be entirely submucosal and therefore undetectable with endoscopy. Clinically unsuspected esophageal verge involvement would upstage a lesion to T4. High-resolution CT has been shown to be a useful adjunct to endoscopy for detection of such submucosal inferior extension.24 Asymmetric thickening of the upper cervical

esophagus may be the only clue to such extension on CT (Fig 6). When CT findings are equivocal, a limited MR study focused on this region can confirm invasion of the inferior constrictor or muscular wall of the proximal esophagus (Fig 6). Extralaryngeal spread (T4). Lateral wall lesions, especially those with apex involvement, frequently invade the thyroid cartilage. When large portions of the thyroid cartilage are destroyed, extralaryngeal spread is usually present. Clinically, it can be difficult to differentiate between a primary hypopharyngeal tumor that extends into the neck and a solitary malignant neck mass. On imaging, extralaryngeal spread is manifested by obliteration of fat planes and displacement and swelling of adjacent structures, including the infrahyoid strap muscles and the thyroid gland. The pharyngeal constrictor forms a relative barrier to tumor spread.

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oropharynx. These tend to be flat thick cancers as observed on axial images and usually cause symmetrical thickening of the entire posterior wall (Fig 11). Because the posterior hypopharyngeal wall is continuous with the posterior wall of the pyriform sinus, lateral spread frequently involves the pyriform sinus, and circumferential submucosal involvement of a pyriform sinus is common. 25 Tumor may extend up into the posterior wall of the oropharynx and even infiltrate the posterior aspect of the tonsillar pillars. A posterior wall tumor may also extend caudally into the proximal cervical esophagus. Cartilage invasion and invasion of the prevertebral muscles is unusual. Although sometimes these tumors show aggressive dorsal spread through the mucosa into the prevertebral musculature and even into the vertebrae. This is an important finding because fixation of the tumor to the prevertebral muscles may prevent complete exision. CT of these tumors frequently shows effacement of the prevertebral fat planes (Fig 11), but the reported sensitivity and specificity of this finding as a criterion for invasion of the prevertebral musculature is low. 26'27 If crosssectional studies show equivocal findings, several investigators recommend fluoroscopic evaluation of the hypopharynx while the patient ingests barium in the lateral projection. This dynamic examination will show whether the an-nor mass moves with respect to the spine. Absence of movement suggests invasion through the posterior wall into the prevertebral musculature. 2.,29 Posterior wall cancer places the retropharyngeal Fig 10. T2 pyriform sinus carcinoma. CT images of a 8.9 cm a squamous cell carcinoma that failed to respond to RT. (A) Section through the mid-pyriform sinus shows the tumor bulk involving the entire right pyriform sinus with extension to the posterior pharyngeal wall, as well as involvement of the aryepiglottic fold. (B) The true cord level shows bulk (8 x 10 mm) involvement of the pyriform sinus apex, with a discrete mass (small arrow) and obliteration of the deep tissue planes (large arrows). There is associated sclerosis of the ipsilateral arytenoid cartilage (A). (Reprinted with permission.4°)

The constrictor muscle fibers attach to the lateral aspect of the thyroid cartilage 1 cm anterior to the posterior cartilage border (Fig 2). This sometimes results in a tumor "wraparound" effect with extensive tumor growth along the external surface of the thyroid without actual thyroid invasion (Fig 7).

Posterior Pharyngeal Wall Carcinoma of the posterior wall of the pharynx commonly involves both the hypopharynx and

Fig 11. Posterior hypopharyngeal wall carcinoma. (A) CT section at supraglottic level shows symmetrical thickening of the entire posterior hypopharyngeal wall and involvement of the left pyriform sinus, The prevertebral fat planes are effaced (compare to Fig 4A). During open neck exploration, no fixation of the tumor to the prevertebral muscles was found.

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nodes at risk. Even if enlarged, these nodes frequently are clinically occult. Detection of these nodes by CT (Fig 8) or MR may completely change the treatment strategy from surgical therapy to (palliative) radiation, or lead to adjustments in radiation portals.

PostcricoiclArea Primary postcricoid carcinoma is rare. These tumors infiltrate in a circumferential manner, narrowing the lumen of the hypopharynx. Much of this growth may be submucosal and visible only with imaging. On axial images, postcricoid carcinoma will typically appear as diffuse thickening of the postcricoid soft tissues, with this thickening frequently extending to involve the cervical esophagus. 25 Often, these tumors extend in the posterior larynx, showing invasion of the arytenoids and cricoid cartilages, causing vocal cord paralysis and hoarseness? IMPACT OF IMAGING OF TREATMENT

This section will discuss the impact imaging findings have in the treatment of patients with hypopharyngeal carcinoma. When there is clinical suspicion (or biopsy proof) of a hypopharyngeal tumor, almost all of these are studied with imaging. Both the primary tumor, as well as the cervical and retropharyngeal nodes, have to be visualized. The radiologist should address the following specific areas in his/her report. 15 1. Local (deep) extent in all directions. Inferior spread of tumor toward the pyriform sinus apex and further submucosal spread toward the esophageal verge/cervical esophagus. 2. Extrapharyngeal spread into the soft tissues of the neck and retropharyngeal space (prevertebral musculature). 3. Invasion of the laryngeal cartilagenous framework. 4. Lymph nodes (location, size, appearance after intravenous contrast administration). 5. Tumor volume.

Surgical Therapy:Impactof lmaging The AJCC staging system has little influence on the surgical treatment of hypopharyngeal carcinomas. Tumors confined to the lateral pharyngeal wall have the same stage regardless of the size and type of resection necessary for adequate treatment. 9 The extent of disease is often underestimated on

endoscopy because of the tendency of hypopharyngeal carcinomas to spread submucosally. Failure to identify the extent of disease results in an inadequate resection. Surgical treatment options include total laryngopharyngectomy, or partial laryngopharyngectomy. However, the majority of patients with pyriform sinus carcinoma are treated with either a total laryngectomy and partial pharyngectomy or partial laryngopharyngectomy depending on the extent of the lesion. 8 The specific issues that need to be addressed when evaluating patients with hypopharyngeal carcinomas are (1) whether the tumor crosses midline, (2) extension of tumor into the apex of the pyriform sinus, (3) presence of cartilage erosion, (4) inferior tumor extension, and (5) invasion of the prevertebral muscles.25 In selected cases, low volume superficial lesions located in the superior aspect of the posterior may be resected with a transoral wide local excision, sometimes requiring a midline mandibulolabial approach. Tumor involvement of the apex of the pyriform sinus is an important factor in carcinomas that arise in this location that are to be treated surgically. The apex of the pyriform sinus is located at the level of the true vocal cords. Because of its close proximity to the cricoarytenoid joint, tumors that involve the apex have a high likelihood of invading the larynx and eroding cartilage. 8,15 Anterior spread of these tumors results in invasion of the cricoarytenoid joint and muscles, thyroarytenoid joint, and paraglottic fat. Because of these factors, pyriform sinus carcinomas that involve the apex are treated with total laryngopharyngectomy, whereas tumors that spare the apex may be treated with partial laryngopharyngectomy. The inferior margin of a tumor and its relationship to the esophageal inlet also needs to be addressed. Invasion of the postcricoid region with extension into the cervical esophagus requires an esophagectomy in addition to a total laryngopharyngectomy. Invasion of the fascia and fixation to the underlying anterior longitudinal ligament is unusual in hypopharyngeal carcinomas. Deep spread into the prevertebral musculature contraindicates surgical resection.15

Definitive Radiotherapy: Impactof Imaging Radiation therapy (RT) is an effective, noninvasive treatment for early (T1, T2) pyriform sinus

IMAGING OF HYPOPHARYNGEALCANCER

carcinoma with local control rates similar to those achieved with conservation surgery. 3°,31 RT, like conservation surgery, allows for the preservation of laryngeal function. Although the continuing debate on whether hypopharynx carcinoma should be treated by surgery or radiation therapy has not yet come to an end, there is growing interest in larynx-preserving therapies. 32-34 Pretreatment computed tomography (CT) volumetric analysis of the primary tumor has been suggested as an effective predictor of local control in a variety of laryngeal tumors treated with RT aloneY -39 Recent investigations have shown that pretreatment CT may also be used in hypopharyngeal carcinoma to identify patients who can be treated with high-dose RT alone. This report, based on 23 patients with T1/T2 pyriform sinus carcinoma, identified tumor volume and involvement of the pyriform sinus apex as two important risk factors in patients who are candidates for treatment with RT alone. The local control rate for tumors with volumes of less than 6.5 cm 3 is 90% (Fig 5), whereas the local control rate for lesions with volumes of more than 6.5 cm 3 is 25% (Fig 10). 40 Tumors with "minimal" (defined as apical involvement less than 10 mm in largest dimensions) or no apical involvement have an 89% chance of local control (Fig 9), whereas tumors with "bulk" apical disease (defined as apical involvement greater than 10 mm in largest dimensions) have a 25% chance of cure when treated with definitive RT (Fig 10). These imaging-based parameters can be combined into a pretreatment CT profile for early (T1, T2) pyriform sinus carcinoma that stratifies patients into groups very likely ("favorable") and those much less likely ("unfavorable") to be controlled at the primary site with definitive RT. Data suggest that the favorable CT profile for a pyriform sinus tumor curable with RT is a volume of less than 6.5 cm 3 and minimal or no apical disease. Patients who fit this profile have a chance of local control of more than 90% when irradiated? ° An unfavorable CT profile (local control < 50%) is either a volume of more than 6.5 cm 3 or bulk apex disease, or a combination of these two risk factors. Patients in this category, who choose to be treated with definitive RT, are at high risk for treatment failure and warrant close follow-up. High-volume tumors and/or bulk apical disease may be best treated with surgery, although a few high-volume lesions were controlled locally (Fig 9). Alternatively, these pa-

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tients may be offered a trial of chemotherapy followed by triage to RT (in good responders) or surgery (in poor responders).32

POST TREATMENT EVALUATION OF THE HYPOPHARYNX

Postsurgical Evaluation The post surgical neck is a difficult area to evaluate because of the extensive anatomic alterations caused by the resection. Surgical resection results in marked distortion of the underlying anatomy, making interpretation of postoperative studies difficult for radiologists who are unfamiliar with their expected appearance. After total laryngectomy, the pharynx has a typical appearance which should be familiar to the radiologist interpreting the postoperative studies. Because the larynx is removed, there are no firm structures or anterior structures compressing the pharynx. Thus, the pharynx is more anteriorly located and more prominent in appearance. The walls of the pharynx are typically not thickened and are usually 2 to 3 mm in diameter. 28 A variety of reconstruction procedures have been developed for curative and cosmetic purposes. After surgery, the defect may be closed by a simple skin closure or some form of myocutaneous flap. There are a variety of reconstructive flaps that are used. One of the more commonly used flaps is placing a portion of the pectoralis flap in the operative defect. With time, the muscle deinnervates, resulting in replacement of muscle by fat. This results in very characteristic radiography with the residual pharynx being suspended and surrounded by a large amount of fat. 28 Another form of reconstruction after total laryngopharyngectomy is a jejunal free flap. Barium studies are the imaging modalities of choice for evaluating the extent of intraluminal recurrences, whereas cross-sectional imaging is the study of choice for detecting submucosal recurrent tumor. 2. The most definitive sign of recurrent tumor is progressive enlargement of a node or along the margins of the surgical resection compared with a baseline study performed after surgery. If prior studies are unavailable, the most reliable signs of recurrent disease are the presence of a focal mass at the primary site or a metastatic lymph node. 28

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Post RT Evaluation The effects of radiation are present in all areas of the hypopharynx, larynx, and neck within the radiation port. In earlier studies a number of histological changes that occur as a result of RT have been described, including varying amounts of edema and fibrosis. 4143As a result of these changes, the radiographic appearance of the irradiated larynx/ hypopharynx is altered considerably compared with the pre-RT findings. Clinical examination of the irradiated hypopharynx is more complicated, owing to these radiationinduced changes, and residual or recurrent tumor may be difficult to detect endoscopically. The radiologist must be aware of the expected post-RT alterations at the primary site and elsewhere so they are not misinterpreted as evidence of recurrent or residual disease. The expected post-RT appearance of the irradiated larynx and hypopharynx on CT, as well as the response of the primary site to irradiation, have been described. 44,45 Generalized (expected) changes include thickening of the skin and platysma, reticulation of the subcutaneous fat, and symmetric thickening of the endolaryngeal tissues. Generalized changes specific for the hypopharyngeal area include increased enhancement of the hypopharyngeal mucosa, retropharyngeal space edema, and symmetric thickening of the aryepiglottic folds (Fig 9C). 44 These generalized changes should not be interpreted as evidence of recurrent tumor. With regard to the primary site response to RT, data suggest that CT may be useful in early differentiation of treatment reponders from nonresponders. On baseline CT studies, performed 3 to 4 months after the completion of RT, three different patterns could be differentiated. Complete resolution of the tumor at the primary site and symmetrically appearing laryngeal and hypopharyngeal tissues are signs that are highly indicative of local control.45These patients require no additional imaging unless further clinical follow-up or concern about treatment failure in the neck warrants CT (Fig 9C). Lesions with partial response (<50% tumor volume reduction) or no response are considered suspicious for local persistence or recurrence of tumor. Immediate further investigation to confirm recurrence is indicated (radionuclide imaging, biopsy). The third group of patients showed a persistent residual mass (between 50% and 75% tumor volume reduction) and/or focal persistent

PAMEIJER ET AL

asymmetry at the primary site. The data suggested that in this "indeterminate" group, about one third of the patients will develop a recurrence. Therefore, these patients should be followed up with careful continued imaging surveillance (along with frequent clinical follow-up visits). A 3- to 4-month time interval is recommended for follow-up CT, to be continued up to 2 years after completion of RT.45 In radiation therapy of the hypopharynx, the entire larynx is included in the radiation field. In a minority of cases, high-dose RT may result in major complications including severe laryngeal edema and/or laryngeal chondronecrosis, which can result in complete loss of laryngeal function. 46 Ultimately, these patients become permanently tracheostomy-dependent or undergo total laryngectomy. The clinical symptoms and signs of laryngeal cartilage necrosis (hoarseness, pain, edema, shortness of breath, tenderness over the cartilage, and foul breath) mimic those of recurrent cancer.46 Furthermore, both conditions can occur simultaneously. Many times, it is impossible to tell if one is dealing with a severe chondronecrosis alone or in combination with recurrent tumor. Although the CT appearance of chondronecrosis is nonspecific, the diagnosis can be suggested when (progressive) laryngeal collapse is observed. The presence of gas bubbles around the cartilage is also suggestive of chondroradionecrosis.47 Alternatively, careful follow-up with imaging might show obvious growth of a laryngeal mass or subclinical adenopathy, indicating that the necrosis is coexistent with recurrent tumor. 25 In such cases, some patients can be salvaged by laryngopharyngectomy. From the foregoing discussion, it should be clear that evaluation of the irradiated larynx/hypopharynx for tumor recurrence and/or treatment-related complications is more difficult than the original evaluation of the untreated larynx and hypopharynx, both from a clinical as well as from an imaging standpoint. Ongoing studies suggest that radionuclide imaging techniques can detect or exclude local recurrence with a higher accuracy than purely anatomic based methods, such as CT and MRIfi

New Imaging Techniques Because tumors are more metabolically active than surrounding tissue, measuring the metabolic activity of an area in question may be potentially more beneficial than purely anatomic information.

IMAGING OF HYPOPHARYNGEAL CANCER

A

489

Before radiotherapy

coronal

B

After radiotherapy

coronal Fig 12. TYR-PET scan of a patient with a T2N1 hypopharyngeal carcinoma. (A) Pre-radiotherapy axial scan showing increased uptake in the primary tumor anterior in the neck. The coronal scan shows an area of increased uptake in the left mid-jugular area, corresponding to the clinically suspected lymph node metastasis. (B) Follow-up TYR-PET scan 3 months post definitive radiotherapy. Both at the primary site, as well as in the left neck, the increased uptake has disappeared. No evidence of recurrence. Because of persistent complaints, endoscopy was performed and multiple biopsies were taken from suspected areas, Examination of these biopsies showed post-radiation fibrosis without signs of malignancy, confirming the negative post-treatment TYR-PET.

Modalities that can separate the metabolic activity of normal tissue and tumor are currently under investigation for attempting to differentiate recurrent tumor from post treatment changes. 49-5° Positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer information on metabolic processes, whereas conventional cross-sectional techniques, such as ultrasound, CT and MRI (mainly) supply anatomic information. The following discussion will focus on PET, the most recent developed technique. In tumor assessment, PET depends on differential uptake of radiolabeled tracers by tumor versus normal tissue. An intravenous injection of the tracer is given and the patient is positioned in the PET scanner. As the radionuclide decays, positively charged particles (positrons) are released. These travel a short distance (1 to 2 mm) before combin-

ing with an electron, resulting in two 511 KeV photons (annihilation radiation) which exit the tissues at approximately 180 ° to each other. The photons are recorded by detectors in the scanner. Because of limiting spatial resolution of the currently used cameras (4 to 5 ram) and uncoordinated tissue transport of positrons before annihilation occurs, anatomic structures are not as clearly defined as shown on CT or MRI. 51 PET allows for three-dimensional reconstructions in every desirable plane, which is an advantage of PET compared with SPECT in which only a two-dimensional plane can be shown. PET is very useful to investigate and image metabolic parameters of tumor tissue. Tracers are chosen to maximize the contrast between tumor uptake and normal tissues. Cancer cells have increased glycolysis compared with normal tissue.

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The increased glycolysis can be monitored with PET, using the glucose analogue 2-deoxy-2[tSF]fluoro-D-glucose (FDG) as a tracer. Although FDG-PET imaging of squamous cell carcinomas in the head and neck may be useful, it is hampered by high false-positive rates owing to FDG accumulation in inflammatory tissues. As an alternative, some centers have started to use llC-labeled amino acids like L-[methyl-nC]methionine (MET) and L-[1-11C]tyrosine (TYR). 52,53 MET mainly visualizes amino acid transport, whereas TYR depicts the protein synthesis rate (PSR) as a parameter for tumor activity in primary tumors and neck nodes. 54,55 After treatment, anatomic changes, edema, and scarring caused by surgery and radiotherapy often make it very difficult to assess whether recurrent or

residual disease is present using clinical examination and conventional cross-sectional techniques. Post-treatment PET can detect, or exclude, residual or recurrent disease with a higher sensitivity (88% to 100%) and specificity (100%) as compared with CT and/or MRI (25% to 77% v s 75% to 80%), because PET depends on differential metabolic activity, whereas CT and MRI rely on changes in the anatomy. 5°,51,56After full-dose radiation of the larynx/hypopharynx, specificity of FDG-PET is decreased owing to FDG uptake in radiationinduced inflammation of the larynx. 57 The value of TYR-PET in the evaluation of the irradiated larynx or hypopharynx is currently under investigation (Fig 12). 55

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