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*Mount Sinai Medical Center, 1994-2003

*Mount Sinai Medical Center, 1994-2003

right or left pyriform sinus, postcricoid area or posterior-lateral pharyngeal wall. If it originates in the pyriform sinus, as most do, it should be noted whether the tumour is arising from the medial or lateral wall, extends to the apex of the sinus or involves the larynx. For tracheal resection, indicate the length of segment excised and whether the tumour is intra- or extraluminal.

Clinical features and diagnostic procedures

A detailed history and physical examination with attention to specific symptoms will often point to the site and extent of the tumour. There are four critical variables that guide the clinician toward the most appropriate course of therapy: pathologic diagnosis, local extent of tumour, status of regional lymph nodes and presence or absence of distant metastasis.

Imaging studies should always preceed endoscopy since the latter procedure often results in edema and a decrease in the accuracy of image studies. Direct endoscopy is not only necessary to obtain a biopsy but also important to further evaluate the extent of the disease and rule out additional primary tumours. Distant metastasis frequently distinguishes surgical from non-surgical candidates. Accordingly, tests for hepatic function and imaging studies of lung and bones are invaluable.

Second primary tumours

Second primary tumours (SPT) are defined as additional primary malignancies that are distinctly separate from the index tumour (IT). Synchronous SPT are diagnosed at the same time, or within six months of the IT. If the SPT is discovered after six months, it is classified as metachronous. The median prevalence of synchronous SPT for the upper aerodi-gestive tract (UADT) is 9% {1027}. The annual risk for SPT, is rather constant and varies between 1.5% {453} and 5.1% {1309} among patients with UADT SCC. The definition of SPT has been further expanded based on molecular markers of clonality or genetic profiling. This includes comparing patterns of loss of heterozygosity (LOH) and specific p53 mutations at various hotspots among IT, SPT and adjacent mucosa. There are drawbacks to comparing only LOH patterns: 1) LOH at various loci can be so frequent, as to be coincidentally present in two tumours, and 2) Progression in genomic loss can be seen with tumour recurrence. This issue is addressed to some extent by p53 mutational analysis, however, identical mutations can occur at various hotspots in 5% of tumours. Some studies have revealed both similarities and discordances in genetic profiling between paired IT and SPT {248}. Concordant genetic profiles of IT and adjacent mucosa support the concept of mucosal field cancerization as a clonal expansion phenomenon in proximity to the IT. So SPT can arise either as related (clonal) events via lateral mucosal spread of premalignant cells, or as genetically unrelated events. Furthermore, there appears to be an indirect relationship between the distance from the IT to SPT, and the time interval between both, and genetic clonality. Thus synchronous multicentric tumours may be explained by the migration or the distant settling of tumoral cells, whereas distant SPT or metachronous tumours would be better explained by the concept of field cancerization. Newly proposed definitions for "true" SPT, local recurrence, second field tumour and metastasis have been proposed based on molecular profiling {248}. "True" SPT are genetically distinct with discordant genetic profiles compared with the IT. If two metachronous carcinomas yield concordant genetic profiles, then the latter tumour is a locoregional recurrence of the former. A "second field tumour" (SFT) distinguishes a second, genetically discordant neoplasm adjacent to the IT, not as a local recurrence but due to the second tumour arising within the same "condemned mucosa" of the IT. The likelihood and site for developing SPT are influenced by the site of the IT. For UADT IT, the most frequent site for SPT is within the UADT {453,1027,1309, 1473,1898}; usually an oral SPT associated with intraoral IT. With respect to the larynx, the risk of developing SPT is higher in patients with supraglottic tumours than in those with glottic tumours {1473, 1898}. Patients with glottic carcinomas are more likely to develop SPT along the respiratory axis (usually lung carcinoma), whereas patients with supraglottic carcinomas are more likely to develop SPT along the aerodigestive axis. No doubt this relates to the specific environmental promoters. The risk of developing SPT clearly correlates with tobacco and alcohol abuse. This risk is more than doubled in patients using tobacco and alcohol, as compared to those patients without exposure {1473}. There is a direct dose-dependent relationship between tobacco and alcohol exposure and risk of SPT development {453,1473}. The risk of developing a SPT after laryngeal IT increased proportionally to the number of cigarettes smoked per day at the time of the diagnosis {1106}. Susceptibility towards the development of SPT can be demonstrated via mutagen sensitivity tests, such as bleomycin-induced chromatid breaks of cultivated lymphocytes {461,462}. Increased muta-gen sensitivity is significantly associated with an increased risk of SPT, with higher risk for both smoking-related and all SPTs (relative risks 2.62 and 2.77, respectively) {2450}. A significantly higher number of chromatid breaks are seen in patients with multiple cancers (mean 1.20) than in patients with a single cancer (mean 0.96) {461,462}. Radiation exposure is also carcinogenic, yet might also have a protective effect on the development of SPT. For patients with laryngeal IT, the latency period for SPT development in irradiated regions was significantly longer than that in non-irradiated patients, suggesting that radiotherapy (RT) may delay the development of SPT {1898}. In patients with laryngeal IT treated by primary RT, the incidence of laryngeal SPT was lower (4.3%) as compared to those patients with laryngeal IT treated primarily surgically, (9.2%), again implying a protective effect {1684}.

Prognosis and predictive factors

Small glottic or supraglottic SCC can be treated conservatively by laser excision, limited resection, or primary radiotherapy (RT), with curative potential, and overall good survival {1605}. RT failures can be salvaged by conservative, potentially curative voice-sparing surgery. Glottic or supraglottic carcinomas that fix the vocal cord(s) can be treated either by primary resection, with possible adjuvant RT, or organ sparing protocols (neoadjuvant chemotherapy with curative RT). If the carcinoma persists or recurs, overall survival is not compromised by delayed, salvage, total laryngectomy. The TNM tumour classification consistently correlates, on multivariate survival analyses, with disease-free and overall survival. Among TNM stage IV patients, extensive cartilage invasion and/or bulky tumour volume are predictors of poor response to chemoradiotherapy; these patients are best treated with primary resection and possible adjuvant RT {1883}. Clinical comorbidities have been demonstrated to significantly affect survival over TNM prognosticators {2041}. The Washington University Head and Neck Comorbidity Index incorporates seven conditions (congestive heart disease, cardiac arrhythmia, peripheral vascular disease, pulmonary disease, renal disease, cancer controlled, and cancer uncontrolled) weighted according to severity, and is a significant predictor of survival.

Generally, histological grading has limited impact on survival. By contrast, the pattern of tumour invasion at the advancing host/tumour interface has been demonstrated, by itself or in combination with other histological variables, to have predictive value for laryngeal carcinoma {290}. Thus within T1/T2 laryngeal SCC, biopsy assessment of the pattern of invasion, may be utilized to predict which patients may respond to primary RT, versus which patients are better treated by primary resection. In multivariate analysis, overexpression of p53 is predictive of improved overall survival {1103}. p53

overexpression and elevated PCNA (proliferating cell nuclear antigen) index have been demonstrated to be significant independent predictors of successful organ preservation {249}.

Hypopharyx

SCC is optimally treated with surgery and adjuvant RT. Prognosis is inversely related to TNM stage and extracapsular spread. {148,1370}.

Trachea

SCC is the most common primary tracheal malignancy, which is usually treated with RT. Poor prognosticators include mediastinal and distant metastases and poor patient performance status {393,1217}.

Squamous cell carcinoma

Definition

Squamous cell carcinoma (SCC) Is the most common malignancy of the larynx, pharynx and trachea. It occurs mainly in adult males who abuse tobacco and alcohol, and is characterized by squa-mous differentiation.

ICD-O code 8070/3

Synonym

Epidermoid carcinoma Epidemiology

See Introduction page 113-114. Etiology

See Introduction page 114-115. Localization

The most common sites for laryngeal SCC vary according to geography, with the supraglottic and glottic regions being the most common locations. Hypopharyngeal SCC originates most frequently in the pyriform sinus, followed by the posterior pharyngeal wall, and the postcricoid area {1053,2661}. Tracheal SCC occurs frequently in the lower third, and less frequently in the upper and middle thirds {1040}.

Clinical features Signs and symptoms

Clinical features depend on the localization of SCC. The most common early symptom in glottic carcinoma is hoarseness. Symptoms of supraglottic, and hypopharyngeal tumours include dys-phagia, change in quality of voice, foreign body sensation in the throat, haemoptysis, odynophagia and neck mass. Dyspnoea, and stridor are especially common in subglottic tumours {749}. Tracheal SCC usually presents clinically with dyspnoea, wheezing or stridor, acute respiratory failure, cough, haemoptysis, and/or hoarseness {2143}.

Macroscopy

Laryngeal and hypopharyngeal SCC may present as a flat plaque with a well-

Post Cricoid Cell Carcinoma

Fig. 3.8 Laryngectomy specimen showing a large hypopharyngeal squamous cell carcinoma occupying both postcricoid region as well as the right pyriform sinus.

Fig. 3.9 Exophytic squamous cell carcinoma. Exophytic bulbous, rounded projections with areas of invasion into the stroma.

Fig. 3.7 Laryngeal squamous cell carcinoma (SCC) of the right ventricular fold (upper) and in the right pyriform sinus (lower).

Fig. 3.8 Laryngectomy specimen showing a large hypopharyngeal squamous cell carcinoma occupying both postcricoid region as well as the right pyriform sinus.

Fig. 3.9 Exophytic squamous cell carcinoma. Exophytic bulbous, rounded projections with areas of invasion into the stroma.

defined, raised edge, or exhibits a polypoid exophytic appearance, which may relate to prognosis. The surface of the tumour is sometimes ulcerated {1711}. Tracheal SCC usually presents as a polypoid mass projecting into the lumen, rarely does it grow as a circumferential or an annular mass {1040}.

Tumour spread and staging

SCC may spread directly to contiguous structures, or via lymphatic and blood vessels to lymph nodes and more distant sites.

Direct spread to contiguous structures

Supraglottic SCC tends to spread into the pre-epiglottic space, pyriform sinus or towards the base of the tongue, but it rarely invades the glottis and thyroid cartilage. Glottic SCC tends to remain localized for a long period; in late stages of the disease, it may extend to the opposite true vocal cord, to the supraglottis and subglottis; it may also extend through the thyroid cartilage and invade the soft tissue of the neck. The subglottic SCC may spread to the thyroid gland, hypopharynx, cervical esophagus and tracheal wall. SCC that crosses the ventricles and involves the supraglottis and glottis, is termed transglottic SCC {1679}. Hypopharyngeal SCC frequently involves the larynx.

Stomal recurrence

Stomal recurrence, defined as recurrent SCC at the mucocutaneous junction of

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