I. Introduction
1.4. Pathology of laryngeal squamous cell carcinoma
1.4.4. Laryngeal squamous cell carcinoma
1.4
The risk for cancer larynx is greatly increased by tobacco smoking and alcohol consumption, an effect which is multiplicative 119‐127. Smoking is the most dangerous risk factor to cancer larynx (average relative risk is about 10 in most of the studies 119‐121), with the risk proportionally related to the smoking rate and duration.
119‐121Cessation of the smoking may reduce the risk up to 60% after a delay of 10‐15 years. 121
Alcohol is identified also as a major risk factor for cancer larynx, the relative risk range being between 1.3 and 4.6 122‐126. Like the smoking, the risk is dose‐ and duration dependent 122‐126. Combination of both smoking and alcohol multiplies the total risk, which may reach 100 with the high levels of consumption of these two risk factors 123,126.
Also the pattern and type of alcohol beverage consumption proved to have a role in the subsite affected within the larynx 123,125,126
. For example, higher wine consumption in southern Europe (France, Italy, and Spain) is associated with an increased frequency of carcinoma of the epilarynx and supraglottis, while the glottic cancer incidence increases in areas where the smoking is the main risk factor 123‐126.
The occupational exposure, dietary factors, gastroesphageal reflux, human papilloma virus, and genetic susceptibility are discussed as minor risk factors, especially in the absence of the major other factors. Their exact implication even as a minor risk factors for laryngeal cancer remains controversial 127.
The history of neck irradiation was discussed also as a minor risk factor, but this is usually described as a rare condition, and related to history of irradiation in young patients 128.
.3. HISTOLOGICAL TYPES OF PRIMARY LARYNGEAL MALIGNANCIES
Primary malignant tumours of the larynx include wide variety (Table 1), but squamous cell carcinoma (SCC) represents the vast majority of the cases 127.
1.4.4. LARYNGEAL SQUAMOUS CELL CARCINOMA
Laryngeal squamous cell carcinoma represents at least 95% of the cases of cancer larynx 129,130. Although it is one of the head and neck SCC the comparative genomic studies, especially regarding p53 polymorphism suggest that it might be more related to lung SCC than to head and neck SCC 130.
Typical squamous cell carcinoma
Verrucous squamous cell carcinoma Basaloid squamous cell carcinoma Spindle (Sarcomatoid) cell carcinoma Adenosquamous carcinoma
Papillary squamous cell carcinoma Variants of squamous cell carcinoma
Acantholytic (Adenoid) squamous cell carcinoma Lymphoepithelial carcinoma (Undifferentiated squamous carcinoma nasopharyngeal type) Giant cell carcinoma (Anaplastic carcinoma)
Mucoepidermoid carcinoma Adenoid cystic carcinoma
Carcinoma ex pleomorphic adenoma Acinic cell carcinoma
Epithelial-myoepithelial carcinoma Salivary duct carcinoma
Clear cell carcinoma Epithelial tumours
Malignant salivary gland –type malignancies
Adenocarcinoma Typical carcinoid tumour (Grade I)
Atypical carcinoid tumour (Grade II) Small cell carcinoma (Grade III)
Combined (Composite) small cell carcinoma Neuroendocrine
tumours
Malignant paraganglioma Soft tissue
malignancies (extremely rare)
Fibrosarcoma ,Malignant fibrous histiocytoma, Liposarcoma, Leiomyosarcoma, Rhabdomyosarcoma, Angiosarcoma, Kaposi sarcoma, Malignant hemangiopericytoma, Malignant nerve sheath tumour, Alveolar soft part sarcoma, Synovial sarcoma, Ewing sarcoma.
Bone and cartilage malignancies (extremely rare)
Chondrosarcoma, Osteosarcoma
Malignant primary haematolymphoid tumours Mucosal malignant melanoma
Malignant germ cell tumours Unclassified tumours
Table 1: Histological types of primary laryngeal malignancies.
1.4.4.1. MACROSCOPY
The macroscopic appearance of the SCC of the larynx is variable; it usually appears as exophytic circumscribed lesion or flat plaque with well defined raised edges, but it may also exhibit a diffuse, endophytic, or a big exophytic polypoid appearance. The colour also may be white, red, or gray and may differ within the
same lesion. The surface is usually irregular and granular, but may be smooth, or ulcerated. Different clinical (macroscopic) terms are used to define abnormalities in the epithelium which help in the description of the tumour or may be present in the precancerous lesions (Table 2) 127,131.
Leukoplakia white patch on the mucous membrane surface.
Hyperplasia thickening and irregularity in the surface epithelium Leukoplasia 1+2
Erythroplakia red patch on the mucous membrane surface.
Erythroplasia 2+4
Keratosis presence of keratin plaques on the surface
Papillary and verrucous extensive irregular epithelial outgrowth (warty like) Ulcer formation Areas of break down in the surface epithelium of the
tissue or the lesion
Table 2: Pathological descriptive terms.
The supraglottic SCC usually presents with exophytic mass with an ulcerated surface. Early glottic SCC presents usually with a limited epithelial lesion, while in advanced cases different aspects are possible:
exophytic, endophytic, or ulcerative mass. Subglottic SCC are rare and resemble the glottic one, while transglottic tumours which involve vertically the three subdivisions of the larynx, tends to be big aggressive and more infiltrative127,131.
1.4.4.2. MICROSCOPY
Invasive laryngeal SCC microscopically resembles other mucosal SCC: the invasion is manifested by the disruption of the basement membrane; keratinisation is present in glottic and subglottic lesions while the degree of keratinisation decreases in supraglottic lesions. The tumours are graded traditionally according to the cellular parameters (the degree of nuclear pleomorphism, mitotic activity, and maturity of cells and nuclei) into well, moderately, and poorly differentiated SCC. The keratinisation usually decreases from well to the poorly differentiated tumours. Most of the laryngeal carcinomas are moderately differentiated 127,131.
Often, one tumour may contain more than one component of differentiation, especially in glottic tumours, which contain commonly a component of in situ or microinvasive carcinoma 131. The role of the differentiation degree is limited as a prognostic factor 127,131,132.
Laryngeal SCC is almost always accompanied by stromal reaction, extracellular matrix deposits, cellular proliferation, and sometimes it is associated with inflammatory reaction. Neovascularisation is frequently seen
127. The invasive front or (tumour border growth) is more important, the growth may be expansive or infiltrative or both 127,131,132
.
Infiltrative borders are more dangerous and more common with the transglottic tumours131. In addition;
endophytic lesions with infiltrative borders, with less marked or no distinct margins tend to metastasize to regional lymph nodes more frequently and rapidly 132.
Perineural, vascular and higher depth of the invasion may increase the risk of lymph node metastases and may be associated with higher incidence of local recurrence 131‐134.
1.4.4.3. GENETICS AND MOLECULAR BIOLOGICAL ASPECTS
In the continuous search to improve the survival in head and neck SCC, several biological markers appeared in the last years 127,130,135‐138. The overexpression of p53 (the name of the tumour suppressor gene located on the short arm (p) of chromosome 17, as well as the protein encoded by this gene) is studied as a prognostic factor in a number of cancer localizations, but till now its prognostic role for laryngeal tumours remains to be demonstrated 130,135. The estimation of the markers Ki‐67 or (MIB1) index and the proliferating cell nuclear antigen (PCNA) as indicators for survival has been widely studied recently but again with contradictory results in laryngeal SCC 135,136. In a similar manner, the overexpression of the epidermal growth factor receptor (EGFR) is investigated in head and neck SCC, as a significant factor in the choice of the treatment and in the prediction of locoregional relapse 137, but in laryngeal SCC the use of this marker still remains debatable 138.