Squamous cell carcinoma comprises more than 90% of all head and neck cancers. Cigarette smoking, alcohol consumption and human papillomavirus (HPV) infection are established risk factors. A painless asymptomatic mass may be the only symptom, whereas numerous complaints may be reported depending on tumor location. The diagnosis is made by clinical and imaging studies. Surgery, chemotherapy and radiation are used based on tumor staging.
Making the diagnosis of SCCHN in its early stages may be difficult, as an asymptomatic course is frequently observed. However, numerous symptoms may be encountered, depending on the location of the tumor. Erythroplakia and leukoplakia, as well as painful mucosal ulcerations may be seen in tumors of the oral cavity, while otalgia, paresthesias, nerve palsies, trismus and halitosis are additional signs of SCCHN . Laryngeal tumors may cause cough, dysphagia, hoarseness and other voice changes. Many patients report a painless mass in the neck , which should be a sufficient sign for a detailed workup. Chronic sinusitis, epistaxis, cervical lymph node enlargement and facial pain may be reported as well.
The first and most important step in the diagnostic workup is a meticulous and detailed physical examination with a particular emphasis on the ear, nose and throat. Anterior rhinoscopy may reveal a tumor in the nasal cavity, whereas indirect laryngoscopy and simple inspection of the sublingual space, but of the lips and other structures as well, may provide enough clues for a detailed investigation. If a clinical suspicion is made based on findings obtained during physical examination, imaging studies such as radiography, CT, or MRI are highly useful in determining the exact location of the tumor and its appropriate stage . To confirm SCCHN, endoscopy followed by biopsy of the tumor is necessary in order to determine optimal therapeutic strategies .
Treatment should be initiated as soon as the diagnosis is confirmed, but only when SCCHN is appropriately staged, as strategies significantly vary . Surgery, chemotherapy and radiation are all used, but prior to their initiation, it is important to correct the patient's nutritional and metabolic status . For early stages, the role of surgery is pivotal and many physicians recommend follow-up radiotherapy for preventive purposes, but currently there are no randomized clinical trials to support its beneficial role . Thus, surgical excision of the tumor is the primary strategy in patients with stages I-II  . In stages III-IV, the combination of surgery (often necessitating reconstructive procedures after tumor excision), chemotherapy and radiation is used  . Platinum analogs such as cisplatin, cetuximab (epidermal growth factor receptor antagonist) or 5-fluorouracil are considered as first-line chemotherapeutic agents . Tumor recurrence is not uncommon, particularly in advanced stages, which is why close follow-ups and appropriate therapeutic measures should be taken, but neither radiation nor chemotherapy have shown long-term success .
SCCHN has a poor overall prognosis, as long term-survival rates are only 50% despite all available forms of treatment . The prognosis is determined based on the TNM classification of tumors at the time of diagnosis   :
If the diagnosis of SCCHN is made in stage I, 5-year survival rates have shown to be as high as 90%, whereas stage IV carries a 40% 5-year survival rate . Based on these findings, the importance of an early diagnosis is pivotal.
More than 85% SCCHNs are associated with alcohol consumption and tobacco smoking , and it is assumed that the malignant genetic mutations are induced by carcinogenic substances and metabolic effects of these substances. Additionally, oncogenic HPVs are recognized causes of oropharyngeal SCCs . Genetic mutations on chromosomes 3,5 and 8 have been observed in both HPV+ and HPV- SCCHNs . Specifically, mutations various proto-oncogenes, tumor suppressor genes ant pro/antiapoptotic genes such as caspase 8, HRS, FAT1, NOTCH, p53, TRAF3 and many other have been identified , and their respective roles in initiation of malignant transformation and subsequent growth have been discovered .
SCCHN is considered to be the sixth most common cancer in the world , with more than 600 000 new cases and 300 000 death documented every year . Various reports have solidified the importance of alcohol, tobacco and HPV infection in the pathogenesis of SCCHN. Namely, 3/4 cases are associated with use of tobacco, (both cigarettes and smokeless tobacco) , alcohol consumption or infection by oncogenic forms of HPV, which is transmitted by sexual intercourse . A strong gender predilection toward males was seen in Europe reports, as incidence rates of 36 per 100 000 males and 7 per 100 000 females were established, respectively . A significant risk factor for SCCHN was determined in patients suffering from Fanconi anemia, especially at a young age .
Abnormal activation of nuclear factor kappa B (NF-κB) through numerous mutations induced by HPV and carcinogens found in tobacco are hallmarks of the pathogenesis model in SCCHN . Mutations of caspase 8, HRAS, FAT1, NOTCH, FADD, TP53 and CDKN2A proteins were observed, which have their respective functions at various stages of the cell cycle - tumor initiation, proliferation, differentiation and progression . Tumor suppressor gene (p53) mutations and abnormal retinoblastoma (RBb)/ARF tumor suppressor pathways have also been determined . The β−catenin signaling pathway, known for its role in maintaining cell polarity and their differentiation is now an important topic of research, as its role in the SCCHN is also considered as important .
The focus on prevention is turned to cessation of tobacco use and overt alcohol consumption. In fact, certain studies have established that almost a quarter of patients would not develop SCCHN in the absence of tobacco and alcohol . Additionally, the introduction of HPV vaccination in the general population may prove to be an important preventive strategy as well . One of the most basic measures of prevention, however, is close monitoring of at-risk patients during their regular check-ups, primarily through carefully performed physical examinations and proper investigations in the setting of high clinical suspicion.
Squamous cell carcinoma of the head and neck (SCCHN) is established as the sixth common malignant disease worldwide , comprising tumors of the oral cavity, nasopharynx, oropharynx, hypopharynx and larynx . Approximately 90% of all head and neck tumors are squamous cell carcinomas, excluding thyroid and skin cancers . Numerous mutations of tumor suppressor and pro-apoptotic genes and aberrations of transcription factors and oncogenes involved in the cell cycle have been observed in the pathogenesis model . Approximately 75% of all SCCHNs are attributed to tobacco smoking, alcohol abuse and oncogenic forms of human papillomavirus (HPV) , and they are considered as the most important risk factors . Epstein-Barr virus was determined as the underlying cause of nasopharyngeal carcinoma in more than 95% of cases. HPV-caused SCC is considered as a distinct clinical entity, primarily because of its higher frequency in younger Caucasian males and much better survival rates compared to tobacco and alcohol-related SCCHN . Additionally, HPV is exclusively contracted through sexual behavior . Epidemiology studies suggest that almost 600,000 new cases and more than 300,000 deaths occur each year worldwide . Such high mortality rates most likely result from a low detection rate in the early stages of the diseases, due to an initially asymptomatic course . Mucosal ulcerations, leukoplakia, nerve palsies, trismus, halithosis, otalgia and pain, depending on the site and location of the tumor may be encountered . To establish a clinical suspicion toward head and neck malignancy, a thorough ear, nose and throat (ENT), as well as neurological exam may be sufficient, whereas imaging studies including plain radiography, computed tomography (CT) and magnetic resonance imaging (MRI) are used for confirmation . Endoscopic examination of the head and neck with subsequent biopsy, however, is considered as the gold standard in diagnosing SCCHN . Imaging studies and biopsy are equally important in determining the clinical stage of the tumor (according to the TNM classification) , as treatment principles significantly vary. Surgery, often with adjunctive radiation therapy, is recommended in milder stages of the disease , while various forms of combined chemotherapy and radiation are used in patients in whom the diagnosis of stage III or IV is made . Despite treatment, the overall survival rate of patients with SCCHN is 50% . For these reasons, preventive strategies through reduction in alcohol consumption and cessation of tobacco smoking, as well as regular screening of at-risk patients, are vital in both early detection and reduction in overall number of cases. The introduction of a HPV vaccine in regular medical practice is an effective measure against several types of HPV-induced cancer, including SCCHN .
Squamous cell carcinoma of the head and neck (SCCHN) is a group of tumors located in the oral and nasal cavity, the pharynx and the neck that share their morphological characteristics, excluding the thyroid and skin malignancies. SCCHN is considered as the sixth most common malignancy worldwide, with more than 600,000 new cases and more than 300,000 deaths every year. More than 75% of cases are associated with either alcohol consumption or tobacco (both in the form of cigarettes and smokeless tobacco), whereas a distinct form of SCCHN, oropharyngeal squamous cell carcinoma, is strongly associated with an infection by human papilloma virus (HPV). Presumably, the presence of carcinogenic substances found inside cigarettes and the effect of alcohol and HPV infection trigger numerous genetic mutations that cause impaired function of proteins involved in various stages of the cell cycle. In addition to tobacco and alcohol, a strong gender predilection toward males has been established. SCCHN has an insidious onset of symptoms, meaning that a significant amount of time may pass before patients report to the physician. In most cases, painful lesions on the tongue and the mucosa of the cheeks or tongue, ear pain, nerve palsies, bad breath, voice changes, nose bleeding and painful swallowing may be reported, depending on the location of the tumor. To make the diagnosis, the physician must conduct a thorough physical examination and support its suspicion by imaging procedures such as radiography (X-rays), computed tomography (CT scan), or magnetic resonance imaging (MRI). Once the exact site of the tumor is found, a biopsy should be performed to obtain a microscopical confirmation. According to the findings obtained by imaging studies and biopsy, this tumor is classified from stages 1 (small diameter without invasion of adjacent structures and lymph nodes) to 4 (severe dissemination into proximal lymph nodes or distant metastases) and once this classification is made, treatment may be initiated. Patients in stages 1-2 may be effectively treated by surgery with adjunctive radiation therapy, whereas advanced stages mandate the combination of surgery, chemotherapy and radiation. The overall prognosis of patients with SCCHN is poor, as long-term survival rates are only 50%. Since the prognosis is in direct relation with the stage (5-year survival rates range from 90% in stage 1 to 40% in stage 4), preventive strategies that include cessation of tobacco use and overt alcohol consumption, as well as HPV vaccination, may significantly reduce the number of cases worldwide. More importantly, physicians need to be aware of this potentially fatal form of malignancy during regular physical examinations of patients who report non-specific ear, nose or throat symptoms, since an early diagnosis yields much better patient outcomes.