In terms of regional metastasis, nodal metastasis transpires when tumor cells at the primary site penetrate lymphatic channels and migrate to regional lymph nodes in the neck, forming a micrometastasis ¹¹ . Lymph node metastasis is a critical prognostic indicator for oral and oropharyngeal carcinomas ¹² . The most common site for OSCC metastasis is cervical lymph nodes, and it reduces the survival rate by 50% ^{13, 14} . Cancer cells usually spread to the lymph nodes on the same side of the cancer primary site. However, contralateral or bilateral lymph nodes metastasis can rarely occur ⁹ . In histopathology, tumor cells dissemination outside the lymph node capsule making the prognosis worse and reducing patient survival rate ¹¹ . Therefore, a thorough head and neck lymph node inspection and palpation for all first-time patients should be performed to help in early detection of cancer, which will increase the chances for successful treatment and improve prognosis ¹⁵ .

For distant metastasis, carcinomas require certain biological events in order to spread from the primary tumor site to an anatomically distant site. Several steps are required for cancer cells to spread from their original site to the metastatic one, as shown in the invasion-metastasis cascade ¹⁶ . The cascade starts at the primary tumor site where the cancer cells locally breach the basement membrane to invade the surrounding extracellular matrix and connective tissue ¹⁷ . Then, the tumor cells move to lymphatic or blood vessels and travel to distant metastatic sites. At this point, tumor cells start to extravasate from the vessels into the stroma of the metastatic site ¹⁸ . Initially, tumor cells use the metastatic tissue microenvironment to grow and form micrometastasis. Then, tumor cells expand and colonize to start their own proliferative program and form macroscopic metastasis ¹⁶ . The lung is the commonest site for distant metastasis for head and neck OSCC ¹⁹ . However, metastasis to other organs, such as mediastinal nodes, liver, and bone, have been also reported ^{19, 20} . Distant metastasis worsens the prognosis and reduces the chances of successful treatment ²¹ . Positive regional lymph node involvement, extracapsular invasion of tumor cells, and human papilloma virus negativity are key factors that increase the risk of primary tumor cell dissemination to distant organs ²⁰ .

The World Health Organization describes “a clinical diagnosis that include any white lesion (plaque or patch) on the oral mucosa that cannot be considered clinically or pathologically as any other disease is a leukoplakia” ²⁵ . In 1975, Waldron et al. reviewed 3,256 clinical cases defined as “leukoplakia” and found that around 80% of the cases are diagnosed microscopically as either hyperkeratosis or acanthosis ²⁶ . They also reported that about 17% of the cases were potentially malignant lesions (12.2% mild to moderate dysplasia and 4.5% severe dysplasia or carcinoma in situ) and the diagnosis of OSCC was made in about 3% of the cases that were received with the diagnosis of “leukoplakia” ²⁶ . Earlier, Bewley and Farwell also reported that OSCC can occur from malignant transformation of leukoplakia ²⁷ . Therefore, early detection of leukoplakia is key to stop their transformation into aggressive malignant OSCC, which could be hard to treat.

PVL is a destructive form of oral leukoplakia that clinically presents as multiple, slowly spreading white lesions with high reappearance rate and high probability of malignant transformation ²⁸ . A study of 47 patients diagnosed with PVL showed that around 40% of the patients developed malignant lesions (OSCC or verrucous carcinoma) during follow-up (within 2 years) ²⁹ . Bagán et al. also reported in their study that there was a high occurrence of patients with PVL developing OSCC in different sites (gingiva and palate being most common) ³⁰ .

Erythroleukoplakia (sometimes called speckled leukoplakia) is a mixed red and white lesion that most likely exhibits more advanced dysplastic changes in histopathological examination compared to leukoplakia ³¹ . This lesion usually has irregular margins, and Candida colonization on these lesions is also common ³² . The chances of speckled leukoplakia for malignant transformation is 18–47% ³³ .

Defined as “Any red lesion of the oral mucosa that cannot be clinically diagnosed as any other condition is called erythroplakia” ³⁴ . True erythroplakia is a more alarming clinical finding compared to leukoplakia. ⁹ A retrospective study showed that 91% of 58 cases clinically observed as “erythroplakia” were diagnosed as OSCC (51%), carcinoma in situ or severe dysplasia (40%), or mild or moderate epithelial dysplasia (9%) ³⁵ . Erythroplakia and leukoplakia are usually predecessors of OSCC ³⁶ and sometimes also seen adjacent to an OSCC lesion ³⁷ .

OSMF occurs due to progressive fibrosis of the oral mucosa due to chronic use of areca nut ³⁸ . Patients diagnosed with OSMF are likely to develop malignant OSCC ³⁹ . A prospective study was carried out on 371 patients with microscopically proven diagnosis of OSCC and it was reported that around 30% of the patients (112) had a history of OSMF ⁴⁰ . However, a study carried out by Chourasia et al. reported an incidence of 4.2% for patients with OSMF transforming to OSCC ³⁹ .

An immune-mediated condition that clinically may present as reticular white areas that may or may not be associated with erosive and ulcerative lesions ⁴¹ . There is still debate whether to consider OLP as a PMDs. A previous study in which the data of 20,095 patients was assessed reported 1.1% incidence of OLP patients developing OSCC ⁴² . It should be noted however, that erosive type of OLP and patients with history of smoking and alcohol use are likely to suffer from transformation of OLP to OSCC ^{42, 43} . It was reported in another previous study that tumour recurrence rate of OSCC is higher in patients who had previous OLP than the patients with primary OSCC ⁴⁴ .

Cigarette smoking helps in the spread of tumors by suppressing immunity and tumor suppressor genes, most importantly p53 and PTEN ⁴⁵ . In an earlier study, al-Idrissi reviewed 65 patients with established diagnosis of head and neck OSCC and reported that the majority of these patients were men and 41.5% were smokers ⁴⁶ . In another study from China, which included 210 cases, a strong association between long term smoking and OSCC was reported ⁴⁷ . Llewelyn and Mitchell from Scotland reported in their study that out of 454 patients with confirmed oral cancer, 60% were smokers and over 95% of those lesions were OSCC ⁴⁸ .

A strong connection between drinking alcohol and several cancer types has been described in the literature ⁴⁹ . The synergetic effects of alcohol consumption and tobacco smoke increases the risk of OSCC by making the oral epithelium more permeable, dissolving tobacco, and promoting its penetration ⁵⁰ . However, chronic use of alcohol alone may lead to OSCC via several mechanisms, including DNA adduct formation, generation of ethanol-related reactive oxygen metabolites, and interference with the DNA-repair mechanism ⁵¹ .

The consumption of shammah is on the rise in many countries ⁵² . It is a combination of powdered smokeless tobacco with ingredients like lime, pepper, ash, and flavoring agents, and people use it by placing it in buccal cavity till the taste penetrates ⁵³ . In a previous study from Jazan, Saudi Arabia, in which data from 132 patients were recorded, it was reported that the most common cancer detected was OSCC followed by thyroid cancer ⁵² . Another study carried out on Yemeni shammah users concluded that there was a strong association between daily shammah usage and formation of leukoplakia (a PMD) ⁵⁴ .

Khat is a plant that is mostly used for chewing and is a mixture of cathine and norephidrine ⁵⁵ . In a previous study, the prevalence of its consumption was found to be 23.1% among university students of Jazan, Saudi Arabia ⁵⁶ . In an earlier case report of one patient, a strong affiliation between khat chewing and growth of OSCC was reported ⁵⁷ . Sawair et al. also reported a strong relationship between khat chewing and development of OSCC in their study, which consisted of 649 Yemeni patients ⁵⁸ . Lukandu et al. reported from Kenya that chronic khat chewing could lead to abnormal epithelial thickening of oral mucosa and increased keratinization, and fibrosis ⁵⁹ .

Shisha is commonly available in restaurants, cafes, and other eatery shops in many countries and it contains a high concentration of nicotine, tar, and carbon monoxide ⁶⁰ . In water pipe smoking, smoke passes through water and there is a general idea that it is less harmful then cigarette smoking ⁶¹ . In a recently published review, a strong association between water pipe smoking and head and neck cancers was reported ⁶² . Zaid et al. reported in a study from Syria and Lebanon that p53 gene mutations were associated water pipe smoking in OSCC ⁶³ . Al-Amad carried out a study in Jordan, which revealed that 36% of their sample who had oral cancer had a habit of water pipe smoking ⁶⁴ .

Exfoliative cytology is a simple method that could prove useful in early identification of oral cancer as it is based on collection of exfoliated cells for microscopic examination ⁶⁵ . It should be noted however that cells can suffer exfoliation normally and/or in the presence of a benign or malignant disease ⁶⁶ . Therefore, the most accurate diagnosis of OSCC should only be made by biopsy.

Despite the new diagnostic modalities in oral cancer detection, biopsy and histopathologic analysis remain the gold standard to diagnose OSCC ⁶⁷ . An adequate biopsy technique involves local anaesthesia administration, having sufficient width and depth of the excised tissue, correct handling of the tissue, and submission without contamination to aid an accurate definitive diagnosis ⁶⁸ .

The typical diagnosis of OSCC is made by clinical oral examination followed by biopsy of the suspected tissue ⁶⁹ . Unfortunately, due to this approach, most OSCC cases either go undetected (at an early stage) or are diagnosed at advanced stages ⁷⁰ . In addition, due to late diagnosis, metastasis for OSCC is very common, resulting in a 5-year survival rate of less than 50% ⁷¹ .

Human saliva could be used for the early detection of various diseases ⁷² . OSCC is very common and its early detection can improve the prognosis significantly ⁷³ . It has been suggested by various researchers that a specific group of protein biomarkers are increased in saliva of individuals with OSCC ⁷⁴ . Franzmann et al. reported CD44 as a probable biomarker of head and neck cancer whereas, Nagler et al. described Cyfra-21-1 and cancer antigen-25 to be potential biomarkers for oral cancer ^{74, 75} . In an earlier study including 395 patients, Elashoff et al. stated an increase in expression of all seven transcriptomes and three proteins as possible markers for OSCC ⁷⁶ . They also reported an increase in the levels of IL-8 and subcutaneous adipose tissue in saliva exhibiting maximum levels of sensitivity and specificity to diagnose OSCC ⁷⁷ . Similarly, Arellano-Garcia et al. described that expression of IL8 and IL1β were increased in saliva of patients with OSCC as compared with control patients ⁷⁸ . Gleber-Netto et al. performed a study involving 180 patients and reported that among the proteomic markers, IL8 and IL1β concentration was greater in OSCC patients when compared with control and dysplasia patients ⁷⁹ . Awasthi performed a study that included 64 individuals with diagnosed cases of OSCC, pre-malignant conditions, and healthy controls ⁸⁰ . It was revealed from the results of that study that patients with OSCC had increased salivary levels of Cyfra-21-1, lactate dehydrogenase, and total protein concentration in comparison to other groups ⁸⁰ .