Leukemia (Blood Cancer)

Oral cancer

Oral cancer describes cancers that originate in the oral cavity.

    The oral cavity includes the lips, the gingiva, or gums, the floor of the mouth, the buccal mucosa which is the soft lining of the inner lips and cheeks, the anterior or front two-thirds of the tongue, the hard palate which is the tough front part of the roof of the mouth, and the retromolar trigone which is the mucosa right behind the last molars on the bottom row of teeth. Behind the oral cavity is the oropharynx. The oropharynx includes the soft palate which is the soft part of the roof of the mouth right behind the hard palate, the tonsils, the walls of the throat, and the posterior or back one-third of the tongue. The oral cavity and oropharynx are lined by epithelium - and there are a few different types.

    The first type of epithelium is called keratinized stratified squamous epithelium. These epithelial cells produce keratin, a protein that makes the layer tough, and protects against normal wear and tear from food and drinks. Beneath the epithelium, there’s another layer called the basement membrane made of tough connective tissue, and below that is the lamina propria which yet a more connective tissue that houses blood vessels, lymphatics, nerves, and immune cells. The oral surfaces covered in keratinized epithelium include the hard palate, the dorsal surface, or top, of the tongue, and the gingiva.

    The second type of epithelium is the non-keratinized stratified squamous epithelium, and it contains cells that don’t produce much keratin, making this layer less tough. The oral surfaces covered by non-keratinized stratified squamous epithelium include the buccal mucosa, the floor of the mouth, the lateral and ventral, or bottom, surfaces of the tongue, the soft palate, and the retromolar trigone. Now the mucosal tissue in the oral cavity can undergo several premalignant pathological changes.

    The first one of these is leukoplakia, where leuko- means white and -plakia means a flat, raised patch or plaque. And leukoplakia specifically relates to a white plaque with no clear underlying cause. These leukoplakias are usually painless but can’t be easily scraped away. Now, the exact cause for leukoplakia is unknown, but a known risk factor is tobacco use. Early on, these lesions are usually pretty thin, so it’s called thin leukoplakia. These can either go away on their own, remain unchanged, or grow and become thicker, at which point it’s called thick leukoplakia. If it becomes bumpy it’s called nodular leukoplakia, and if it becomes wart-like it’s called verrucous leukoplakia. 

    Now a more serious form of leukoplakia is called proliferative verrucous leukoplakia, which usually affects women, with no risk factors it has a predilection for gingiva and causes multiple rough white lesions that grow and spread, and in most cases, eventually develop into squamous cell carcinoma. At the cellular level, leukoplakia typically shows a thickened keratin layer. Since keratin absorbs water, a thick keratin layer looks white when it’s wet. At a cellular level, leukoplakia may show cells that have undergone some degree of dysplasia, meaning they look abnormal in some way, but are not cancerous, or malignant, yet. However, leukoplakia is considered a precancerous condition, meaning that compared to normal tissue, it’s more likely to develop into cancer in the future. And that change could happen at the microscopic level, meaning that the lesion might look the same on the outside, even though the cells have become cancerous. Generally speaking, the transition from dysplastic cells to malignant cells occurs gradually. And as cells become more and more dysplastic the lesions sometimes develop red spots, and at that point, it’s called erythroleukoplakia.

    Cells in these red areas have suffered serious damage to their DNA and don’t mature normally and therefore can’t produce keratin. And as they become more and more atypical, the more immature becomes the epithelium and it will start becoming thinner or atrophic and allow more of the underlying blood vessels to be seen through the mucosa.

    At that point, the lesion will be completely red and will be called erythoplakia. Erythroplakias are more serious than leukoplakia because almost always when they are removed and examined under the microscope they will show severe dysplasia or early cancer.

Now, a lesion that looks like leukoplakia, but isn’t, is an area of frictional keratosis. That’s where there’s repeated physical trauma like rubbing the tooth surface against the mucosa of the cheeks. For example, after a dental procedure that leaves a rough tooth surface, or a broken tooth rubbing against the mucosa. It’s a normal hyperplastic response, meaning the epithelial cells in the area divide more than usual and build up a protective layer of keratin. It’s a bit like developing a callus on your hands after spending the weekend raking leaves. An area of frictional keratosis is not a precancerous lesion and usually fades away once the irritation stops.

    

Most of the oral cavity is lined by stratified squamous epithelium, so the majority of cancers that arise are squamous cell cancers. Squamous cell cancers arise from squamous cells that undergo genetic mutations that either activate proto-oncogenes or inactivate tumor suppressor genes. When proto-oncogenes, like epidermal growth factor receptor and ras, are activated, it turns them into oncogenes that promote cell division. And when tumor suppressor genes, like the genes that encode proteins p53, p16, and the retinoblastoma protein, also called pRb, are inactivated, it removes the inhibition to cell division.

    So together there’s uncontrolled cell division which can give rise to a tumor. As the cancer cells divide they can sometimes gain the ability to penetrate through the basement membrane, and at that point, it’s considered a malignant tumor. The malignant cells can then invade surrounding tissues like the salivary glands, muscle, and even get into the blood and lymphatic systems, and metastasize, or travel, to other areas of the body. It’s a bit like a toddler learning to get out of the crib and then running rampant through the house. Proliferative verrucous leukoplakia can turn into a particular type of squamous cell cancer called verrucous carcinoma, and it’s also sometimes called snuff dippers cancer since it is more common among users of snuff and other forms of chewing tobacco. 

    Generally speaking, malignant cells are irregularly-shaped with darkly staining nuclei, enlarged nucleoli, and produce abnormal keratin that looks like pearls - so they’re called keratin pearls. It’s thought that most of the time, co-carcinogenesis is necessary to cause oral squamous cell carcinoma. That means that more than one carcinogen, or causative factor, is needed to cause the disease - like abusing alcohol and using tobacco. Many carcinogens come into contact with a wide area within the oral cavity and oropharynx, so the idea is that they cause field cancerization. This means that the entire contacted area or field undergoes genetic changes and is more likely to develop cancer in the future.

    In addition to squamous cell carcinomas, other types of oral cancers include adenocarcinomas, which develop in glandular cells like those of the salivary glands beneath the mucosa, extranodal lymphomas which develop in lymphocytes, and melanomas, which develop in melanocytes, found all over the mucosal epithelium, but most often in the hard palate. Squamous cell carcinoma is also known to arise at the lip vermillion in those who smoke, right at the location where a person holds the smoking device, such as a cigarette or pipe.

    However, most lip vermillion cancers result from chronic sun damage and are associated with actinic cheilitis, a precancerous rough patch on the lip. The most common locations for oral cancer are the lateral and ventral surfaces of the tongue and floor of the mouth, and the lower lip vermilion because it’s exposed to more sun than the upper lip. Well-known risk factors for oral squamous cancer include tobacco smoking, alcohol abuse, chewing betel quids or paan, UV radiation, exposure to metal dust or chemicals like phenoxy acetic acid; vitamin and mineral deficiencies, like severe form of iron-deficiency called Plummer-Vinson syndrome, and various immune deficiencies. Oropharyngeal cancers are strongly associated with infection by human papillomavirus type 16, but interestingly, tumors of the oral cavity, like the lateral tongue and floor of the mouth are not usually associated with HPV 16.

    The symptoms of oral cancer include numbness or changes in sensation in the mouth and throat, a hoarse voice, pain or difficulty with chewing or swallowing, and both painless and painful lumps, sores, or discolorations in the mouth that don’t heal. Signs of precancerous development include areas of leukoplakia, erythroplakia, erythroleukoplakia, or any other abnormal appearing tissue or masses. In other words, white or red lesions without an obvious traumatic source and have a rough, irregular, velvety, or speckled surface - are the ones to look out for. As the tumor grows some become exophytic, where it grows outward, or endophytic, where it grows inward. Diagnosis typically includes a biopsy of the tissue because cancer has to be confirmed histologically.

    A lymph node biopsy and imaging such as an X-ray, CT, or combination imaging like a PET/CT might be necessary for tumor staging. The staging system consists of T, for the primary tumor’s size and involvement of surrounding structures or muscles; N, for the number and location of involved lymph Nodes; and M, for Metastasis which denotes whether the distant spread of cancer has occurred or not. Generally speaking, the higher the number assigned to either of these components, the higher the stage, and worse the prognosis. While the prognosis of squamous cell carcinoma in the oral cavity depends largely on the tumor stage, HPV status is a main prognostic factor for squamous cell carcinoma in the oropharynx. Treatment of precancerous lesions begins with active surveillance, removing any diseased tissue, and stopping any causative agents, like smoking and alcohol abuse.

    Malignant lesions are mainly treated by surgery, but some cases also require chemotherapy or radiation therapy. And ideally, these lesions are caught early so that they can be better managed. That’s why it’s important to screen for oral cancers like with a routine head and neck exam in the dental office. That’s where it’s good to look for early lesions which are often red or white plaques with an unknown cause. 

    All right, as a quick recap... Oral cancer refers to cancers that originate in the oral cavity, which is lined by keratinized or non-keratinized stratified squamous epithelia. Leukoplakia is a precancerous white lesion, but more serious lesions include the red-colored erythroplakia which almost always contain severe dysplasia or early cancer. 

    Risk factors for oral cancer include alcohol abuse, tobacco smoking, using betel quid, immunodeficiency, and nutritional deficiencies.

    Diagnosis includes a biopsy, while treatment might include surgery, chemotherapy, or radiation therapy.