I. Introduction
1.4. Pathology of laryngeal squamous cell carcinoma
1.4.5. Local spread
The results of the early studies of the injections of dyes and radioactive isotopes, introduced the hypothesis of compartmentalization and submucosal subsites of the larynx 48. Furthermore, embryological data of the development of the submucosal connective tissue layers and compartments of the larynx explain this hypothesis and point to submucosal barriers which may affect tumour spread in the larynx especially in early cases 41. In 1961 a detailed histological study of serial sections of the laryngeal cancer cases was introduced as a basis to observe the behaviour of cancer of the larynx 139.
A big review 140 of the experimental and clinical anatomical studies of the spread of cancer larynx, concluded that 140:
• cancer of the larynx mainly spreads by direct extension, prior to lymphatic spread and more rarely follows the vascular and neurological routes;
• the larynx should be considered as a highly compartmentalized organ in which, five compartments on each side are identified;
• the submucosal compartments on each side are completely separated from those of the other side, and both are sharply demarcated from the submucosal tissue of the trachea;
• laryngeal cancer spread follows the line of least resistance, and thus, the growth tends to be limited to the compartment of origin by the fibers bounding the compartment;
1.4.5.1. GLOTTIC AND TRANSGLOTTIC TUMOURS
Laryngeal SCC originating from the glottis accounts for close to 60% of all laryngeal cancer cases 141,142,
with the exception of south Europe, where supraglottic carcinoma including epilarynx are more common than glottic carcinoma 125,127.
Glottic carcinoma originates from the epithelium of the vocal fold in the vast majority of the cases (more than 95%), especially the anterior two thirds 131,142. Initially it usually spreads along the vocal fold mucosa without deep infiltration, and tumours tend to go anteriorly towards the anterior commissure rather than posteriorly (Figure 26) to the area of the arytenoid 38,142,143.
Figure 26: Diagrams of the larynx: midcoronal section (1a) and midsagittal section (1b) showing glottic tumour spread.
Tumour spread is represented by the black spot at the vocal cord level. H: hyoid bone, TC: thyroid cartilage, CC: cricoid cartilage, E:
epiglottis, A: arytenoid, T: trachea. In figure 1a the thick black arrows indicate the common routes of spread in early glottic cancer, while the red thin arrows show the next steps when the cancer becomes more advanced, the thin blue interrupted arrows indicate the less common routes in early cases. In figure 1b the thick arrows indicate the common routes of spread in early glottic cancer, while the red interrupted thin arrows show the less common routes.
• ANTERIOR COMMISSURE EXTENSION
While pure carcinoma originating from the anterior commissure is a rare condition (1%) 38,142, extension of glottic cancer to the area of the anterior commissure is common, ranging from 20% to 50% in different studies 38,142,144,145. When the cancer reaches the anterior commissure it becomes very close to the subglottis
38,45,144 , and to the thyroid cartilage (the distance between the vocal cord mucosa and the thyroid cartilage is about 2‐3 mm) 38,45.
When the tumour reaches the anterior commissure: 1) it can pass along the mucosa to the opposite side, usually slightly at a subcommissural level; 2) it can spread down or less commonly up 143,144.
After anterior commissure invasion, deep invasion is limited superiorly and superolaterally by the very strong anatomical fibrous arrangement of the anterior commissure ligament layers and the thyroepiglottic ligament which act like a basket to stop cancer extension. In rare cases, when cancer invades into this area it invades easily the thyroid cartilage and rapidly the preepiglottic space 36,79,143‐147
. Therefore, anterior
commissure invasion is more commonly associated with a downwards extension to the subglottic area immediately below the anterior commissure, where no fibrous barriers are present 38,143,144. From this site the tumour usually spreads in the anterior subglottis and becomes easily in contact with the thyroid cartilage, which becomes at a higher risk 143,144,147.
Thus, most glottic tumours extend anteriorly and inferiorly in the anterior subglottic area which is a weak zone, with a thin submucosa adherent to an ossified cartilage 30,31,79,144,147. Invasion of this zone is associated with a high incidence of cartilage invasion and extralaryngeal extension (Figure 27) though the cricothyroid membrane 30,31,143,147
. The weakest spot in this zone is the narrow paramedian area between the median cricothyroid ligament and the anterior border of the cricothyroid muscle where the tumour faces only a delicate fibrofatty tissue pierced by the vascular structures 30,31.
• LATERAL EXTENSION
Less commonly, glottic tumours can spread to the subglottis directly along the mucosa without deep infiltration 143,144,146,147. Commonly invasion proceeds first through the vocal ligament, followed by the medial and lateral parts of the thyroarytenoid muscle, up to the fat of the paraglottic space which is adjacent to the thyroid cartilage 143,144,146
. These different degrees of invasion can be inferred from the clinical examination of vocal fold mobility, from the early disturbance of the cordal mobility, up to the complete fixation of the vocal fold 39,143.
Less commonly the cancer can extend along the ventricular mucosa to reach laterally the paraglottic space143. Whatever the route of the spread, when cancer larynx reaches the paraglottic space it becomes rapidly a transglottic cancer 39,46,143. Transglottic cancers usually invade the thyroarytenoid muscle and fix or severely impair the vocal fold mobility 39,143,146. In addition, they spread down to the upper part of the subglottis, between the conus elasticus and the thyroid perichondrium, usually causing a bulge in the lateral infraglottic cavity 46,143,146,147
. Since no barriers are found in this location, the cancer can easily pass anteriorly to extralaryngeal tissues 31,44,46 or proceed posteroinferiorly to the area of the cricoarytenoid joint and the surrounding muscular attachments, causing fixation of the arytenoid 31,39,44,46. Finally, tumours can spread superiorly (less frequent), lateral to the ventricle and the ventricular band, causing bulging of the aryepiglottic fold and, rarely, breaking through the supraglottic mucosa, this extension usually occurs late with a highly advanced glottic tumour 46,143.
When transglottic tumours (Figure 27) reach the thyroid cartilage, the thyroid perichondrium restricts cartilage invasion for the vast majority of the tumours until a very advanced stage (transglottic tumours 3 cm or larger, or glottic tumours with more than 1 cm subglottic spread) 143.
The lateral barrier separating the anterosuperior part of the paraglottic space from the preepiglottic space is still a matter of debate 33,44,46.
At the glottic level the posterior extension along the paraglottic space is limited early by the attachments of thyroarytenoid and lateral cricoarytenoid muscles (where they come nearly in contact with each other), however with the advancement of the invasion the cancer invades deeply these muscles fixing both the vocal fold and the arytenoid. Moreover, the cancer becomes so close to the submucous tissue of the angle of the piriform sinus which becomes at risk for invasion 31,39,44,46
.
Extension of the glottic tumors to the mucosa of the posterior glottis is not common and occurs usually in advanced cases and transglottic tumours. The invasion proceeds through the vocalis muscle, lateral to the vocal process of the arytenoid rather than by direct posterior extension along the mucosa 144,146.
Figure 27: Diagrams for the larynx midsagittal section (2a) and midcoronal section (2b) showing the transglottic tumour spread and the common routes for cartilage invasion and extralaryngeal spread.
H: hyoid bone, TC: thyroid cartilage, CC: cricoid cartilage, E: epiglottis. In figure 2a, the red arrows indicate the common routes of spread anteriorly, usually at the lower part of the thyroid cartilage or through the cricothyroid membrane. In figure 2b, the red arrows indicate the common routes of extralaryngeal spread and cartilage invasion, usually at the postero‐inferior areas of the thyroid cartilage and the adjacent area of the cricoid cartilage.
1.4.5.2. SUPRAGLOTTIC TUMOURS
As discussed above (§4.5.1), supraglottic SCC exhibits high variation in incidence: in North America it accounts for 30‐40% of all laryngeal cancers 141,142, while it is nearly equally distributed in Europe 125,127. The primary site of origin is globally the same, the supraglottic endolarynx accounts for most cases, while epilaryngeal or laryngeal margin lesions are less common 125,127,141,142
. In regions with high incidence of supraglottic carcinoma, such as southern Europe, the relative incidence of the epilaryngeal lesions increases.
125,127
In supraglottic endolaryngeal SCC, the laryngeal surface of the epiglottis is the most common site of origin, followed by the false vocal fold, while the ventricle is a rare site of origin. In epilaryngeal lesions, the aryepiglottic fold is the more common site of origin, followed by the tip and lingual surface of the epiglottis, and finally the arytenoids, which are the rarest site 141‐143.
Supraglottic SCC spreads more up than down and more anteriorly than posteriorly. Anteroinferiorly, the
1.4.
thyroepiglottic ligament stops the vast majority of the lesions except in the rare cases of big ulcerative lesions.
Along the inferolateral margins, supraglottic tumours routinely pushes the ventricles inferomedially, giving the wrong impression of a transglottic mass but it rarely invade the ventricles or the glottis itself 143,146‐149.
The basis of this clinico‐pathological finding is not completely clear and the presence of lateral glotto‐
supraglottic barrier has been debated. 150 However, the clinical and pathological observations in addition to the high success rate of supraglottic laryngectomy provide a relative evidence that the supraglottic tumours do not invade the glottis until late stage 143,144,147,149
.
As tumours extend cranially, an anterior growth into the preepiglottic space occurs easy through the pits in the epiglottis, followed by an extension to the mucosa and muscles of the base of the tongue. The hyoid bone, hyoepiglottic membrane, and thyrohyoid membrane are rarely invaded, even in advanced cases involving the base of tongue and preepiglottic space 143,146,149‐151
.
Thus the supraglottic cancer remains limited to the supraglottis until very advanced stage and thyroid
cartilage invasion in supraglottic cancer is extremely rare 143,146,147,149
. Cartilage invasion usually occurs in rare conditions, when a transglottic lesion develops from a supraglottic tumour (which travel along the lateral wall of the paraglottic space to invade the intrinsic laryngeal muscles, the glottis, and behaving like the transglottic tumours), or in big ulcerative lesions eroding the anterior commissure tendon 146,149,150
.
Carcinoma that originates from the epilarynx tends to creep over the mucosa to the surrounding extralaryngeal structures, like base of tongue, oropharynx and piriform sinus. Generally they are more aggressive than the typical endolaryngeal supraglottic cancer, the worst being lesions originating from the aryepiglottic fold because they tend to extend towards both larynx and piriform sinus 143,149,150.
5.3. SUBGLOTTIC TUMOURS
Carcinoma originating from the subglottis is a rare entity, representing about 2 % of all laryngeal SCC
141,142,152. When the lower surface of the vocal fold is included the incidence increases to 5% 152.
Subglottic carcinoma usually presents late, and spreads mainly circumferentially along the subglottic mucosa and towards the vocal fold muscles. When it advances it has a high tendency to spread to the cartilages, extralaryngeal soft tissue, trachea and thyroid gland 142,152,153.
1.4.5.4. CARTILAGE (FRAMEWORK INVASION)
Cartilage invasion in cancer larynx usually occurs in advanced cases. Transglottic tumours have the highest incidence, around 50%, while in glottic tumours cartilage invasion is found in 20% of cases 146,154.
The perichondrium and the cartilage itself are very strong barriers to invasion, while the ossified cartilage is a weak spot 154,155. Invasion usually occurs at the areas with advanced ossification thus framework invasion is a better term than cartilage invasion 145,155. The most common sites for framework invasion are the lower margin of the thyroid ala, and the upper surface of the cricoid arch (Figure 27) 143,146,147,154,155.
Whatever the supraglottic cancer size, it never invades the framework when confide to the supraglottis
146,154
.
Cartilage invasion can occur as a single one or combination, thyroid cartilage is affected in the most cases, also it is the most cartilage affected alone 155.
The anterior part of the lower border of thyroid ala is the most affected part by invasion, transglottic tumours usually invades the lower border of thyroid and or the upper border of cricoid 143,146,147,154,155
. The invasion can take different forms from erosion up to growing through, but a rare form of growth can occur also which includes small erosion followed by intracartilaginous spread when the perichondrium is intact over an
ossified cartilage and this also supports that the perichondrium is a strong barrier against spread 154,155.
Figure 28: Diagrams for the larynx midcoronal section (3a) and midsagittal section (3b) showing supraglottic tumour spread.
Supraglottic tumour spread is represented by the black spot (1) at the epiglottis and red spot (2) at the ventricular band. H: hyoid bone, TC: thyroid cartilage, CC: cricoid cartilage, E: epiglottis, A: arytenoid, PES: pre‐epiglottic space, T: trachea. The thick arrows indicate the common routes of spread, while the thin interrupted arrows indicate the less common routes.