Squamous cell carcinoma (SCC) of the oral cavity is one of the most common malignancies of the head and neck. Risk factors for the development of SCC include infection with human papillomavirus (HPV), tobacco use, and alcohol use. HPV-positive SCC of the oral cavity is more commonly seen in young adult patients, whereas HPV-negative disease is more prevalent in older patients with histories of alcohol and tobacco use. We describe the case of a young adult with an extensive history of vaping using nicotine-delivery systems who was diagnosed with HPV-negative SCC that was rapidly progressive and fatal.
Cancers of the head and neck are a heterogenous group of malignancies involving the oral cavity, oropharynx, nasopharynx, hypopharynx, larynx, paranasal sinuses, and salivary glands.1 Oral cavity and pharyngeal cancer is the most common site of malignancy in the head and neck and is the sixth most common malignancy worldwide.2 The average age at diagnosis is 63 years of age, and only 0.4% of all cases occur in individuals <20 years of age.3 Treatment of oral cavity cancer and pharyngeal cancer is guided by TNM (tumor, node, metastases) Classification of Malignant Tumors staging and involves primary surgical resection or radiotherapy for localized disease and multimodal therapy involving surgery, radiotherapy, and/or chemotherapy for advanced disease.4,5 The prognosis of oral cavity cancer is generally poor because of high rates of recurrence, with a 5-year survival rate of 66% and >10 000 deaths per year in the United States.3,6,7
The development of oral cavity cancer is highly related to environmental factors, including tobacco smoking, alcohol use, and infection with human papillomavirus (HPV).8 HPV is a well-established risk factor for the development of squamous cell carcinoma (SCC) of the oral cavity and is commonly seen in younger patient populations when compared with HPV-negative SCC.8 HPV-negative SCC reveals a strong association with tobacco and alcohol use, as well as various driver mutations in TP53, FAT1, CASP8, NOTCH1, CDKNA, and HRAS, among others.8,9 Over the past 20 years, the incidence of HPV-negative oral cavity cancer has decreased, likely because of public health smoking cessation campaigns and other related tools.1 During this time, electronic cigarettes (e-cigarettes), also known as electronic nicotine-delivery systems, have gained massive popularity worldwide, especially among youth and young adults.10 Vaping refers to the use of e-cigarettes to create an aerosol by heating up a liquid containing a solvent (propylene glycol, glycerin, or both), flavors, and liquid nicotine (although nicotine may be absent).11
There are currently 4 generations of e-cigarettes, all of them containing the following 4 basic components: a cartridge or a pod that holds e-liquid (often with various flavorings), a heating element known as an atomizer, a battery, and a mouthpiece for inhalation. The most popular form of e-cigarette is the Juul, which is shaped like a USB drive and constitutes 73% of the e-cigarette market at present.12 The liquid nicotine used in Juul is made from loose tobacco leaves, which contain much higher doses of nicotine (59 mg/0.7 mL of liquid).12 The nicotine in 1 Juul pod is roughly the equivalent of the nicotine in a pack of cigarettes, according to Juul Laboratories.12
Although tobacco smoking is a well-known risk factor for the development of HPV-negative SCC of the oral cavity, the role of vaping in the oncogenic process has not been well established. We describe a young adult with an extensive history of vaping and no other carcinogenic risk factors who developed aggressive, poorly responsive HPV-negative SCC of the oral cavity.
Case
A previously healthy 19-year-old male patient presented with a nonhealing left lateral tongue ulcer after accidentally biting his tongue, leading to a wound that progressively swelled over the next month. He was prescribed amoxicillin and prednisone. Over the next 2 weeks, his swelling remained stable, and he was prescribed a second course of amoxicillin and prednisone. He was referred to an otolaryngologist, who diagnosed him with an abscess. Over the next week, he started to experience progressive swelling, pain, and deformity of the tongue despite the antibiotic and steroid treatment. He also reported new-onset trismus, dysphonia, and radiation of pain inferiorly to the mandible and bilaterally into the temporomandibular joints.
He returned for a follow-up, at which he was found to have a large ulceration of the left side of his tongue (Fig 1) that crossed the midline and palpable right cervical adenopathy. Review of systems was positive for bleeding, neck swelling, weight loss, and ageusia. Initial blood count and chemistries were unremarkable. A computed tomography scan revealed an invasive left tongue lesion with extension into the floor of the mouth and multiple bilateral necrotic lymph nodes with spread involving the left internal jugular vein. A tongue biopsy was performed, which revealed poorly differentiated invasive SCC. Polymerase chain reaction test results for HPV were negative. Additional history was positive for smoking 0.5 packs of cigarettes per day for 1 year 4 years before his diagnosis, at which point he started vaping daily using nicotine-delivery systems and Juul. The quantity of cartridges or pods per day is uncertain. He denied previous use of other illicit drugs but started to use marijuana 2 to 3 times weekly after receiving the diagnosis.
After we received the results of the biopsy, further workup with a positron emission topography scan revealed an extensive lateral tongue lesion with bilateral cervical nodular spread (right 1B, left 2 and 3) and narrowing of the left and right carotid arteries, 10% and 47%, respectively. Tumor staging revealed a stage IV tumor (cT4aN3b[N2c]M0). Immunostaining revealed neoplastic cells positive for p40 and negative for p16 and desmin. The patient underwent a total glossectomy with left anterolateral thigh flap reconstruction, resection of bilateral lateral pharyngeal walls, right selective neck dissection, left modified radical neck dissection, and tracheostomy. He recovered well after the procedure and was discharged 13 days postoperatively. Two days after discharge, he was readmitted for an initial episode of syncope. He was diagnosed with dehydration in the setting of emesis and poor nutritional intake and was brought back to the operating room for gastrostomy tube placement.
During the next month, he continued to experience multiple syncopal episodes, and repeat imaging revealed findings concerning for recurrence, including multiple new soft tissue masses in the right sublingual and left parapharyngeal and carotid spaces, along with erosion of the right mandible. His recurrent syncopal episodes were thought to be related to mass effect over the carotid, for which cardiology was consulted and Holter monitoring performed. He was subsequently started on adjuvant radiotherapy without improvement. MRI of the oral cavity (Fig 2) revealed extension of the primary tumor to involve the anterior third of the oral tongue, bilateral lingual neurovascular bundles, and extra nodal metastatic adenopathy invading the carotid artery wall and the carotid bifurcation. Because of progressive growth of the tumor, radiotherapy was discontinued, and the patient was started on salvage chemotherapy with weekly paclitaxel and carboplatin and had improvement and stabilization of symptoms allowing for discharge after 1 28-day cycle. He received a subsequent cycle outpatient, before care was transferred to an adult facility, and monotherapy with pembrolizumab was started. The patient ultimately developed metastatic disease and died 6 months after diagnosis from an acute cardiorespiratory event.
MRI of the oral cavity with and without gadolinium-based contrast reveals amorphous signal abnormalities within the left neck surrounding a long segment of the cervical internal carotid artery and extending laterally and inferiorly with invasion of the sternocleidomastoid muscle.
MRI of the oral cavity with and without gadolinium-based contrast reveals amorphous signal abnormalities within the left neck surrounding a long segment of the cervical internal carotid artery and extending laterally and inferiorly with invasion of the sternocleidomastoid muscle.
Discussion
Since being introduced into the market in 2004, e-cigarettes have been promoted as a safe alternative to cigarettes and a means of smoking cessation.13 E-cigarette use has been declared an epidemic by the Center for Disease Control because it has been associated with >2600 cases of severe lung injuries and. >60 deaths across the nation.14,15 Most fatal cases were associated with Tetrahydrocannabinol use.15 Although vaping-related lung injuries have been well documented in the literature, the correlation between e-cigarette use and increased risk for developing cancer has not been studied.
Commercially available nicotine solutions contain numerous chemicals besides nicotine, including diethylene glycol, ethylene glycol, formaldehyde, acrolein, and various heavy metals (nickel, tin, silver, and aluminum).16 There is substantial evidence that chemicals present in the aerosols are capable of inducing DNA damage and mutagenesis, supporting the hypothesis that e-cigarette aerosols could increase the risk for cancer.17 In a study conducted by Ganapathy et al18 exposing human oral cells to e-cigarette aerosols, the authors found short-term dose-dependent DNA damage with e-cigarette aerosols, likely due to oxidative stress and direct cytotoxic effects, and this effect was independent of nicotine concentration. From these results, it can be inferred that components other than nicotine included in e-cigarette aerosols are responsible for causing DNA damage and can do so even with short-term use. These findings have also been replicated in many other studies revealing cell death and DNA double-strand breaks in cell lines exposed to short-term treatment of e-cigarette aerosols independent of nicotine.19,20 Furthermore, exposure of e-cigarette aerosols was found to decrease the transcription of proteins essential for DNA damage repair in human oral cells, further increasing cancer risk.18 DNA damage is the main initiator of cancer and is also implicated in other chronic diseases, including neurodegenerative disease and cardiovascular disease.21 From these results, it can be inferred that e-cigarette aerosols are carcinogenic and contribute to both direct DNA damage and the failure of DNA repair mechanisms.
Although most flavorings in e-liquids are designated as safe by the Food and Drug Administration, these designations are for oral consumption in food and there have not been studies investigating potential toxic effects of inhaling these flavorings.17 In several studies in which e-liquid flavorings have been investigated, flavored e-liquids, especially menthol, were found to be more cytotoxic than e-liquids without flavorings and caused increased DNA damage, inflammation, and oxidative stress.22 Possible chemical irritants that may be responsible for this increased cytotoxic effect include nitrosamines, aldehydes, polycyclic aromatic hydrocarbons, tobacco alkaloids, volatile organic solvents, and trace metals.16 These data are concerning, considering flavored e-cigarettes are especially popular among youth and young adults.
Our patient started using marijuana after receiving his diagnosis, which may have contributed to his poor prognosis and rapid decline. A large population-based study found a positive association between marijuana use and the development of oral cancer.23 Marijuana may act additively or synergistically with nicotine in inducing carcinogenic molecular changes; in multiple studies, a significantly higher prevalence of squamous metaplasia and atypical cells have been found in individuals who use both marijuana and tobacco when compared with those who use each agent alone.24,25 Recently, there have also been several studies in which an association between microbiome alteration and the development of oral cavity SCC has been reported.26 Both marijuana use and nicotine exposure have been found to alter the oral microbiome, potentially contributing to our patient’s disease process.27
The association between vaping and the development of oral cavity cancer has not been well studied in clinical practice. Given the rarity of this disease in patients <20 years of age and the absence of HPV infection, our case suggests that e-cigarette use may pose a carcinogenic effect and may lead to the development of oral cavity cancer. Because vaping is a relatively new phenomenon, there is a lack of studies and reports investigating the long-term health effects of e-cigarette aerosols. Further molecular studies are needed to elucidate the relationship between e-cigarette aerosols and oral cavity cancer. This case supports the hypothesis that vaping can cause cancer and there should be heightened awareness about both the short- and long-term health risks of vaping. We hypothesize that this patient’s frequent vaping through nicotine-delivery systems increased his risk for developing SCC through the direct carcinogenic effects of inhaled toxins present in nicotine solutions on oral cavity cells.
Drs Indelicato, Katzenstein, and Klawinski provided the clinical care for the patient, conceptualized the report, and revised the manuscript; Mr Breslin and Dr Hanna collected the patient data and contributed to the writing of the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
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