Etiopatogenia cancerului de hipofaringe

Introduction

The malignant tumours of the hypopharynx represent 0.6-1% of the total number of malignant tumours and 7-10% of the malignant tumours of the ENT sphere. This disease has caused quite a stir among oncologists, this illness tending to continually increase in morbidity^(1,2).

Several factors contribute to the outbreak of hypopharyngeal cancer (risk factors): smoking, alcohol consumption, the increase of the environmental pollution, untreated enduring pathological processes (chronic pharyngitis, dyskeratosis of the pharyngeal mucosa)^(3,4).

The most important risk factor is smoking. In 98% of the cases the patients have been abusive smokers for 15-20 years. Regarding the distribution by gender, it has been noticed that, if in the past the incidence of the hypopharyngeal cancer was greater in men, the difference between the genders has decreased nowadays up to 3/1, compared to the growth of smoking incidence in women. It can be generally encountered on adulthood with a maximum frequency at the age of 40-60 years old. In 85-90% of the cases the diagnosis is established in stage III-IV and only in 10-15% of the cases in stage I-II. In 45-60% of the cases the primary lesion is associated with a satellite metastasis adenopathy in the lymphatic cervical ganglions, which prove a very unpleasant treatment prognosis.

The recent findings in the molecular medicine have shown that neoplasm is a genetic disease, the development of the neoplastic cells being a consequence of the disruption of the proliferation, differentiation and apoptosis mechanisms.

The features of the cancer cell are: autonomous proliferation, inhibition of cell growth suppressors, apoptosis avoidance, unlimited replication, angiogenesis, tissue invasion and metastasis^(5,6).

The etiology of hypopharyngeal cancer

Many studies conducted worldwide have established the influence of “lifestyle” in the appearance of cancer. Through “lifestyle” we usually understand the eating habits, smoking, alcohol consumption, the environmental factors, pollution (physical, chemical or biological), the influence of some viruses, the genetic predisposing factor, the metabolic and hormonal factors, the organism immunity, and the psycho-emotional factors.

Some harmful eating habits, such as the inges­tion of concentrated alcoholic drinks, associated with the consumption of food with oncogenic potential, inappropriately prepared (smoked, fried and canned food), to which the cigar smoke is added, increase the incidence of hypopharyngeal cancers.

Tobacco - the tars resulting from tobacco burning contain carcinogenic hydrocarbons involved in the appearance of the pharyngolaryngeal cancers. When smoking, approximately 4000 chemical substances are released as gas or particles which present a carcinogenic potential. Polycyclic aromatic hydrocarbons, nitrosamines, aldehydes, benzene and butadiene have the greatest carcinogenic risk.

The appearance of “light cigarettes”, with sophisticated filters and with reduced quantities of tar and nicotine, have decreased the incidence of cancer only by 26% compared to the consumption or traditional cigarettes.

The smoke of the cigarette also affects the “pas­sive smoker”, who unwillingly inhales the smoke that others produce. Recent statistics show that a non-smoker wife living next to a husband who smokes 20 cigarettes a day has the same possibilities of developing cancer as her smoker husband.

Although smoking is a risk factor unanimously accepted, not all the people exposed will develop the disease, which leads to the idea that there are individual varieties with respect to the cancer likeliness and a genetic polymorphism which modulate the association between exposure and cancer.

The fight against smoking aims at persuading people that not smoking is the normal state, and society must know that tobacco and its products are one of the avoidable causes of disease and death⁽⁷⁾.

Alcohol represents an independent and synergic smoking factor, with the role of promoting the mutagenic effects of the tobacco carcinogenic substances, supporting their dissolving in the body through the vasodilatations it produces.

Generally, due to the fact that alcohol metabolism implies a great consumption of vitamins, vitamin deficiencies, malabsorption and nutritional deficiencies appear.

A genetic polymorphism of the vitamins which metabolize the alcohol and the tobacco has been discovered to represent a major source of mutagenic agents that cause lesions at the level of the cell’s DNA, and alcohol reduces the effectiveness of the DNA repair mechanisms, which would be necessary after the mutagenic agents have harmed it. Thus, we can explain the propensity for multiple primary tumours in smokers and alcoholics^(3,4).

The gastro-oesophageal and laryngopharyngeal reflux, a frequent pathology of modern man, has been associated with the development of malignant tumours in the postcricoidian region. The existence of an esophagitis facilitates the action of carcinogenic chemicals following the pattern: esophagitis - mucosal atrophy - dysplasia - cancer.

In women with Plummer-Vinson syndrome, coming from Scandinavia and Ireland, a growth of the incidence of the oesophageal and hypopharyngeal cancer has been noticed through a mechanism of a chronic irritation associated with the deficiency of C vitamin and iron^(1,2).

The Human Papilloma Virus types 16 and 18 show their carcinogenetic effect through the viral oncoproteins E6 and E7, which inactivate the tumour suppressor proteins p53 and Prb. The role of the HPV virus type 16 can be independent from the action of other carcinogens. The HPV-positive tumours are more frequently encountered in non-smoker persons who do not drink alcohol and do not present immunosuppression, being basaloid or poorly differentiated tumours^(5,8,9).

The association between HPV and laryngeal cancer highly influences its prevention, treatment and prognosis. The presence of the HPV virus represents a factor of positive prognosis through the immune supervision it determines, the tumours responding better to irradiation, chemotherapy or both of them^(5,10).

At present, the contribution of the genetic factor to the development of the hypopharyngeal cancer is investigated. The modifications of the genotype and the phenotype linked to the tobacco metabolism, the abnormalities of the DNA repair mechanism, as well as other carcinogens can be susceptibility factors to hypopharyngeal cancer.

For cancer to develop, six fundamental pheno­mena must be present: self-sufficient proliferation, insensitivity to anti-proliferation signals, and tissue invasion with metastasis.

Genetic events such as mutations, gene deletions, chromosomal rearrangements, which lead to some irreversible genetic modifications, have been highlighted^(1,2).

The psycho-emotional factor is unanimously admitted in the multifactor complex of oncogenesis.

Violent psychic traumas, stress, negative inner states of low intensity but repeated, and permanent conflict states induce negative modifications on the general adaptation syndrome of the organism to hormonal and immunological disturbances, very significant in the increase of the oncogenetic potential. The limitation of the psycho-emotional factor’s effects is one of the prophylaxis means for which our resources are practically unlimited. All the resources call on the psychic balance which can be obtained through determination, education and wisdom^(1,2).

Nutrition - epidemiological and experimental studies recognize that nutrition plays a direct role in the etyology of digestive cancers.

Some food, especially of animal origin, can contain a series of oncogenic factors. To these we add the ones resulting from the methods of preparing and preserving food (smoked and fried food, additives, used in food preserving, such as aflatoxins, nitrosamines and cyclamates)

A fat-laden nutrition, the abuse of calories, the lack of milk-based products, cereals, vegetables and fruits, the lack of vegetal fibres in the food ration play an important role in oncogenesis. A series of food have cancer protection: food of vegetal origin, fruits, milk-derived products, bran cereals, high fibre germinated cereals, food high in vitamin A, beta-carotene and vitamin C. The protective anti-cancer effect of vitamin A has been proven. Citrus fruits and vitamin C protect the mucosa of digestive pathways against cancer.

Vitamin E and B are given a carcinogen role, but totally unproven up to present^(1,2).

The professional risk factors can be: the asbestos, wood dust, paints, nickel, and glass wool.

Usually, in the organism appear daily about 1 mil­lion mutant cells. These are normal cells with antigenic attributes and with oncogenic potential. They are neutralized - destroyed by the normal immune apparatus of the organism, this way leading to a healthy balance. But under the influence of one or several from the aforementioned factors, the destruction of the mutant cells becomes impossible or is incompletely done. Thus, the cells which are not destroyed become malignant⁽¹¹⁾.

Pathogeny of hypopharyngeal cancer

The hypopharynx is covered on the whole surface by a Malpighian epithelium, therefore most of the cancers at this levels are differentiated Malpighian carcinoma (spinocellular epithelioma).

Macroscopically, the tumours of the hypopharynx start with an infiltrative process which can ulcerate (the ulcero-infiltrative form) and it is characterized by an invasion of the mucosa, with more or less profound destruction of the subjacent structures (glands, muscles, membranes, cartilages) or by the appearance of adenoid growths (the vegetant form). This form develops at the surface without affecting profound tissues, being a carcinoma isolated at the mucosa, but which spreads at the distance, affecting all or only part of the pharyngeal epithelium. We can encounter a combination of these processes, the ulcero-vegetant form⁽¹²⁾.

The tumour dissemination is realized contiguously, by lymphatic, or rarely hematogenous pathway. The spreading direction of the hypopharyngeal cancer is determined by the existence of some zones of adherence which constitute an obstacle to the tumour growth⁽⁶⁾.

The cancer of the anterior angle of the pyriform sinus extends towards the sinus slopes and towards the aryteno-epiglottic fold or to the lateral wall of the pharynx.

The cancer with the starting point on the external side of the aryteno-epiglottic fold extends towards the ventricle bands inside the larynx and to the profound part of the pyriform sinus.

The retro arytenoid and retro cricoid carcinomas extend towards the aryteno-epiglottic folds and to the endolaryngeal mucosa of the cricoid signet ring.

The cancer of the external wall of the pyriform sinus extends upwards to the pharyngoepiglottic fold and the posterior pillar and downwards to the pharyngoesophageal junction.

The cancer of the aryteno-epiglottic fold extends backwards to the pyriform sinus, frontwards to the glossoepiglottic vallecula and outside towards the side wall of the pharynx.

The cancer with the starting point at the poste­rior side of the hypopharynx extends upwards to the oropharynx or downwards to the pharyngoesophageal junction.

The most important tumour dissemination way is the lymphatic one. When there is an invasion of a cervical lymph nodes group, which makes them clinically distinguishable, it is possible that the cancer cells have seized other lymph nodes which are not yet palpable, by contiguity, and the fact of not removing them leads to evolutions and clinical stages with more guarded prognosis. The distant metastasis of the hypopharyngeal neoplasm can develop in the liver and the lungs.

Cancer is a genetic disease in which the genes involved in the cell functions undergo point mutations, deletions, chromosomal rearrangements, which lead to the appearance of some genetically irreversible modifications. This genetic damage comprises the activation of proto-oncogenes and the inactivation of the suppressor genes.

The oncogenes, when activated, determine the malignant phenotype, and when inactive, they are called proto-oncogenes, and they play a role in the normal activity of the cells. The oncogenes activation is produced after some qualitative functional modifications such as the development of an unaltered or qualitative factor, such as the production of an altered factor.

The suppressor genes prevent the uncontrolled growth and differentiation of the cells.

Cancer development requires the concomitance of six fundamental phenomena: autonomous prolifera­tion, inhibition of the cell growth suppressor, apoptosis avoidance, unlimited replication potential, angiogenesis, tissue invasion and metastasis.

The autonomous proliferation is realized by the expression of some EGFR (Epidermal Growth Factor Receptor) growth factors and receptors of the aberrant growth factors. The growth signals are produced through diffusible signalling molecules (growth factors), extracellular matrix components, and cell-cell interactions. The growth signals are transmitted from the cell surface towards the nucleus through different pathways^(13,14).

The inhibition of cell growth suppressor - the cell cycle is the process through which the cell duplicates its DNA and divides under the control of a group of molecules called cyclins. Every molecule that affects and regulates the cyclins will interfere with cell growth process and it is a potentially carcinogenic mediator.

The TP53 gene is the most analysed gene involved in carcinogenesis. It is located on the short arm of chromosome 17, the presence of deletions at this level leading to a progression towards cancer. Other cyclins that interfere in the cell cycle are: the retinoblastoma protein (RB), the INK4 gene family (P16, P17, P18, P19), the D1 cyclins’ family, the P21 family (P21, P27, P57)^(5,9).

The apoptosis avoidance - the gene p53 has an important function in cell cycle regulation, DNA repair and the apoptosis mechanism. The mutation appearing at the level of the gene TP53 leads to the survival of the DNA altered cells and to the genome instability.

The apoptosis effector cells are proteases from the caspase family, divided in three groups: the caspases without apoptotic role (1, 4, 5, 11, 12, 13), initiator (apical) caspase (8, 9, 10) which initiate and amplify the cascade and effector (executioner) caspases (2, 3, 6, 7), final effectors of apoptosis⁽¹⁵⁾.

The unlimited replication potential - tumour cells have the ability to maintain the length of the telomeres, indefinitely multiplying.

Angiogenesis is fundamental for tumour growth and for metastasis. Angiogenesis and neovascularisation process encompassed several stages which are regulated by stimulating and inhibitory factors. The stimulating factors are:

• Vascular Endothelial Growth Factor (VEGF)
• Basic Fibroblast Growth Factor (bFGF)
• Platelet-Derived Endothelial Cell Growth Factor (PD-ECGF)
• Interleukin 8 (IL-8).

The inhibitory factors are interferon (IFNa and IFNb) and the thrombospondins  (TSPs)^{(13,14,16,17)}.

Tissue invasion and metastasis imply three important steps: tumour cell attachment to the basal membrane, proteolysis of extracellular matrix and migration of tumour cells. Both normal squamous epithelial cells and neoplastic cells present on their surface specific receptors for the basal membrane: integrins, E-cadherins and catenins.

The proteolysis of extracellular matrix is a stage of the tumour invasion and depends on a series of proteolytic enzymes^{(13,14,16,17)}:

• the matrix metalloproteinases (MMPs);
• the urokinase-type plasminogen activator (uPA);

the family of serpins.

Conclusions

Together with the laryngeal cancer, the hypopharyngeal cancer represents one the most common neoplastic pathologies from otorhinolaryngology. The epidemiologic worldwide studies show that smoking is a very important risk factor involved in the outbreak of this cancer. The genetic factor is essential in the appearance of the disease.