2.2.1 Betel Quid Chewing

Betel quid chewing represents a modifiable risk factor that increases the risks of both oral premalignant lesions and OCC. “Betel quid” refers to combinations of betel leaf, areca nut, and slaked lime, with or without the addition of tobacco leaf, which is then chewed or packed into the gingivobuccal sulcus of the mouth. Various combinations of these ingredients can be made into betel quid, or each ingredient can be consumed individually. ¹² Sweeteners and essences, such as menthol, are also commonly added to betel quid. Betel quid formulations are highly variable by region and may have different designations based on composition. Mass-produced betel quid substitutes, known as pan masala (which does not contain tobacco) and gutka (which contains tobacco), are also widely available. ¹³ Given the variability in content, when the term “betel quid” is used, it is important to determine the formulation’s specific components. In particular, the addition of tobacco further increases the risks of betel quid. For example, a meta-analysis of 25 studies from the Indian subcontinent showed a relative risk of OCC of 8.47 for betel quid with tobacco, compared to 2.41 for betel quid without tobacco. ¹⁴ It is also important to note that the concomitant use of alcohol or cigarette smoking with betel quid chewing increases the risks of oral premalignancy and OCC in a synergistic manner. ^{15 , 16}

Global estimates of betel quid use indicate that there are currently nearly 700 million consumers worldwide. ¹² The chewing of betel quid in different forms, a custom which dates back thousands of years, has become deeply ingrained in a number of sociocultural traditions. The earliest use of betel quid as a masticatory object dates back to 430 BC. Indian scripts dating back to the 4th century indicate that betel quid was originally thought to be a therapeutic agent and was used to treat a wide range of human disease. It was also recognized for its euphoric and stimulant effects. ¹⁷ The highest rates of betel quid use are clustered in the countries of India, Pakistan, Bangladesh, Sri Lanka, and Taiwan. In these areas, up to 40% of the population use betel quid in various forms. ¹⁸

Premalignant oral lesions associated with the use of betel quid include leukoplakia, erythroplakia, oral submucous fibrosis, and lichen planus. ^{12 , 19 , 20} The presence of leukoplakia or erythroplakia secondary to betel quid use is common and has been associated with an increased risk of oral malignancy. Betel quid use can also lead to oral submucous fibrosis, a premalignant condition characterized by subepithelial inflammation and fibrosis (▶ Fig. 2.1). The rate of malignant transformation of oral submucous fibrosis to carcinoma has been estimated at 8% over a 17-year period. Moreover, patients with oral submucous fibrosis may be up to 400 times more likely to progress to malignancy compared to tobacco users without premalignant lesions. ¹² Nonmalignant consequences of oral submucous fibrosis also exist and contribute to morbidity. Depending on the degree of fibrosis, oral submucous fibrosis can result in trismus, dysarthria, limited ability to provide oral hygiene, and limited food consumption leading to malnourishment. In particular, trismus may complicate surveillance and surgical resection of dysplastic or malignant lesions. These considerations should be taken into account when initiating treatment plans for patients with OCC secondary to betel quid use. ^{12 , 21}

In addition to increasing the risk of OCC, betel quid use also increases the risk of malignancies of the esophagus, larynx, lung, liver, and pancreas. ²² A dose-dependent relationship exists between the duration and amount of betel quid use and the risk of malignancy. Given these risks, patients who utilize betel quid should undergo increased surveillance of oral lesions, and clinicians should maintain a heightened suspicion for carcinoma. Furthermore, patients should receive counseling on the risks of use and the benefits of cessation, as the cessation of betel quid use reduces the risk of malignancy by up to half. ¹⁴

2.3.1 Fanconi Anemia

Fanconi anemia (FA) is a rare, autosomal recessive disorder caused by mutations in any of at least 15 known genes, each involved in deoxyribonucleic acid (DNA) repair and stabilization pathways. Defects in these pathways lead to chromosomal instability and thereby increase the risk of malignancy, including lymphocytic and myelocytic cancers, as well as solid organ tumors. ²⁵ FA is also characterized by bone marrow failure and sensitivity to DNA cross-linking agents. Acute myeloid leukemia is the most common malignancy associated with FA. However, as the life expectancy of FA patients has improved due to advances in leukemia management, the incidence of solid organ tumors has risen to as high as 28% by 40 years of age. ²⁶ Solid tumors in FA patients occur most commonly in the head and neck, the majority of which arise in the oral cavity. The incidence of head and neck SCC is 240- to 700-fold greater in FA than in the general population, ^{27 – 29} and OCC comprises over two-thirds of head and neck cancers diagnosed in FA. ³⁰

In individuals with FA, OCC and other head and neck cancers are known to be aggressive and carry a poor prognosis. ²⁶ The propensity of FA patients to develop OCC, coupled with poor tolerance of radiation therapy and chemotherapy, underscores the need for careful and frequent screening, starting as early as late childhood, in this population. ^{26 , 30}

2.3.2 Dyskeratosis Congenita

Dyskeratosis congenita (DC) is a rare inherited disorder caused by defects in telomere maintenance. The most common form of DC is X-linked recessive, but autosomal dominant and autosomal recessive forms have been observed. ³¹ Clinically, it is characterized by bone marrow failure, premature aging, and increased risk of malignancy. Patients with DC present with a triad of mucocutaneous findings: oral leukoplakia, reticulated hyperpigmentation of the skin, and nail dystrophy. Leukoplakia affects up to 80% of patients with DC and most commonly affects the oral mucosa (▶ Fig. 2.2). ³² The leukoplakia associated with DC can affect any mucosal subsite within the oral cavity and is considered a premalignant condition. ³¹ Secondary to the increased propensity for oral leukoplakia, the risk of OCC is significantly increased in DC, with an incidence of tongue cancer 1,154-fold greater in patients with DC than in the general population. ³³ Given the increased frequency and early onset of premalignant mucosal changes in DC, up to 35% of oral cancer malignancies arise in the third to fifth decades of life in these patients. Individuals with DC therefore require close surveillance of leukoplakic lesions, to ensure early detection and treatment of malignancy. ³⁴

2.3.3 Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder characterized by hypersensitivity to ultraviolet radiation, secondary to defective nucleotide excision repair mechanisms. ²³ Individuals with XP are at increased risk of developing skin cancers, with 50% of patients developing cutaneous malignancies between the ages of 10 and 14 years. The majority of malignancies associated with XP occur on the face, scalp, lips, and eyelids. However, other sites, such as the oral tongue or gingiva, can be affected. SCC affecting the anterior tongue, presumably resulting from sun exposure to the tip of the tongue, is estimated to occur over 20,000-fold more frequently in XP patients under the age of 20 compared to the general population. In addition, malignant neoplasms arising from oral cavity sites other than the tongue occur 400 times more frequently in young XP patients than in the general population. ^{35 , 36} Patients with XP therefore require close surveillance with frequent and thorough examination of the skin, lips, and oral cavity. Early identification and treatment of premalignant or malignant lesions are imperative.