Oral Squamous Cell Carcinoma and Human Papilloma Virus (HPV): A Silent Threat.
Dr. Farhat Naz, Ph.D.
Background:
According to Global cancer statistics 2022: GLOBOCAN , the oral squamous cell carcinoma is one of the most common cancers of the oral cavity in India (F. Bray et al, 2022;Coelho KR. et al, 2012). It is a major public health problem because many patients arrive late for treatment. The disease affects the mouth lining, especially the buccal mucosa, tongue, gums, and floor of the mouth. In the Indian subcontinent, the burden is high because tobacco chewing, smoking, and betel nut use remain widespread. These habits continue to drive most cases of oral cancer (Singh MP et al, 2016).
We have studied 800 patients with oral squamous cell carcinoma at a tertiary care hospital. It examined the relation of p16 immunopositivity and HPV DNA status in a large Indian cohort (Naz F et al, 2016). Our study is valuable because it gives a broad picture of the disease pattern in real clinical practice. The study also shows how oral cancer can have more than one cause. Tobacco remains the dominant risk factor, but HPV may contribute in a subset of cases (Bouda M et al, 2000)
The oral cavity is easy to inspect, yet this cancer is still often diagnosed late. That happens because early lesions may be small, painless, or mistaken for minor ulcers. Many people ignore symptoms until eating, speaking, or swallowing becomes difficult. In advanced disease, the cancer may already have spread to nearby tissue or lymph nodes. This delay affects survival, treatment planning, and quality of life (M. Awadallah et al, 2018).
Our study reflects a wider change in head and neck oncology. HPV-related cancers have risen in some regions, especially in the oropharynx (Dediol E et al, 2016). That has made researchers ask whether HPV also has a role in oral cavity cancer. In our study, p16 positivity was found in 17.37% of cases. Among those p16-positive cases, 74.8% were HPV DNA positive for HPV-16 or HPV-18. These findings suggest that HPV may be important in a smaller but meaningful group of patients (Naz F et al, 2016).
The patient profile was also interesting. Most patients were between 40 and 60 years of age. The disease was more common in men, which fits the usual pattern of oral cancer in India. Tobacco smoking and tobacco chewing were the major habits. Yet the study also showed p16 positivity in younger patients who had no tobacco habit. That finding is important because it suggests a different biological pathway in some patients.
Symptoms:
Oral squamous cell carcinoma may begin with very mild symptoms. A small ulcer may appear in the mouth and fail to heal. A patch of redness or whiteness may also appear. Some patients notice a rough area, a lump, or a thickened patch on the cheek or tongue. These early signs are often ignored because they may not cause pain (Koppikar et al., 2005).
Pain is not always present at the start. This makes the disease easy to miss. As the lesion grows, pain becomes more obvious. It may burn during eating or brushing. A patient may also feel irritation while speaking. The discomfort may slowly increase over time. What began as a minor mouth sore may become a persistent and troubling lesion.
The disease can also affect function. Chewing may become difficult if the tongue, cheek, or jaw area is involved. Swallowing may hurt when the lesion enlarges. Speech may become unclear if the tongue is affected. Some patients may notice bleeding from the lesion. Others may develop a foul smell from the mouth because of tissue breakdown and poor hygiene (Singh MP et al, 2016; M. Awadallah et al, 2018).
Loose teeth can sometimes be an early clue. A person may visit a dentist because of unexplained tooth mobility. A non-healing extraction site is also suspicious. In more advanced disease, a neck swelling may appear because the cancer spreads to lymph nodes. Weight loss may occur as eating becomes painful. Patients may also avoid food because of fear of pain, which worsens weakness and malnutrition.
Our study showed that buccal mucosa and the anterior two thirds of the tongue were the most common sites involved (Jiang X et al, 2019). This fits the common pattern of tobacco-related oral cancer in India. The lesion may also occur on the lip, hard palate, soft palate, floor of mouth, alveolus, or retromolar trigone. Rare sites like the retromolar trigone and gingivobuccal sulcus showed high HPV positivity in this study, although the number of cases was small. That finding needs more validation.
Symptoms can also vary with the stage of the disease. Early disease may be silent or very subtle. Middle-stage disease may cause pain, difficulty in opening the mouth, or trouble in chewing. Late-stage disease may produce ulceration, bleeding, marked swelling, and neck node involvement. Because the symptoms can be mild at the start, awareness is essential. A mouth ulcer lasting more than two weeks should never be ignored.
Diagnosis:
Diagnosis starts with careful clinical examination of the oral cavity. The doctor must inspect the lesion closely. Its exact site should be noted. This is important because cancers of the oral cavity and oropharynx can sometimes be confused. In the study, accurate documentation of the biopsy site was emphasized to reduce misclassification.
The most important diagnostic step is biopsy. A tissue sample is taken from the suspicious lesion and examined under the microscope. The study used hematoxylin and eosin staining for routine histopathology. This confirms squamous cell carcinoma and shows the basic tumor structure. Histology also helps determine whether the tumor is well differentiated, moderately differentiated, or poorly differentiated.
Our study then used p16 immunohistochemistry. p16 is often used as a surrogate marker of HPV-related disease (Gayatree A et al, 2020). It is not perfect, but it is widely used in head and neck pathology. In this study, moderate to strong nuclear staining in more than 75 percent of tumor cells was taken as positive. That cut-off follows accepted criteria in HPV-associated cancer work. The antibody clone used was E6H4, which is commonly used in pathology practice.
HPV DNA testing was done by PCR in p16-positive cases. This helped identify whether the tumor carried high-risk HPV DNA. The study found HPV-16 and HPV-18, either alone or together. Some cases also showed co-infection with other high-risk HPV types. However, the kit could not specify exactly which other types were present. This means the data point to HPV involvement, but they do not prove that HPV caused every positive tumor(Naz F et al, 2016).
The study also showed that p16 positivity does not always equal HPV-driven cancer. This is an important point. p16 may rise in tumors through non-HPV pathways too. That is why p16 should be interpreted carefully. The paper noted that p16 immunopositivity was higher than HPV DNA positivity. This pattern has been seen in other studies as well. It supports the idea that p16 alone is useful, but not definitive.
Histologic differentiation was also studied. Most p16-positive and HPV-positive tumors were moderately differentiated. Well-differentiated and poorly differentiated tumors made up smaller groups. The study found no strong correlation between HPV status and tumor grade. This means HPV positivity did not predict how differentiated the tumor looked under the microscope. The grade alone was not enough to define viral involvement.
The TNM stage was also recorded. Many p16-positive and HPV-positive cases were in stage IVA. Even so, there was no significant link between HPV status and stage. This suggests that HPV positivity in oral cavity cancer does not clearly define early or late disease in the same way that it sometimes does in oropharyngeal cancer. Clinical stage still remains a key factor in planning treatment.
We looked at age, sex, habits, residence, religion, marital status, education, occupation, family size, and diet. No significant correlation was found with most of these factors. However, urban patients had a higher rate of p16 and HPV positivity than rural patients. Some younger patients without tobacco habits also had higher p16 positivity. This may indicate a distinct subgroup in which HPV plays a more important role(Naz F et al, 2016).
Treatment:
Treatment depends on the stage, site, and spread of the tumor. Surgery is usually the main treatment when the lesion is operable. The surgeon removes the cancer with an adequate margin of healthy tissue. If the neck lymph nodes are involved or at risk, neck dissection may also be needed. In many cases, reconstruction is necessary after tumor removal to restore appearance and function (Laco J et al, 2012).
Radiotherapy is also widely used in oral squamous cell carcinoma. It may be given after surgery to reduce the chance of recurrence. It may also be used as the main treatment if surgery is not possible. Chemotherapy can be added in advanced disease, especially when radiation is being used. These treatments are often planned together in a multidisciplinary team.
The paper did not test treatment outcomes directly. Even so, its findings have treatment value. Many cases were already in advanced stage, especially stage IVA. This shows why early diagnosis matters so much. Early-stage disease usually needs simpler treatment and has a better chance of cure. Late-stage disease is harder to manage and often causes more functional loss.
Treatment is not only about removing the tumor. It is also about helping the patient live better during and after therapy. Pain control is important. So is nutrition support, because oral cancer can make eating very difficult. Patients may need soft food, liquid supplements, or even feeding support in severe cases. Mouth care is important during treatment because the oral mucosa can become sore or infected (M. Awadallah et al, 2018).
Speech and swallowing rehabilitation may be needed too. The tongue, jaw, and soft tissues can be affected by surgery or radiation. That can change speech, chewing, and swallowing. A patient may also need psychological support because oral cancer can affect self-image and social life. These supportive steps are part of complete treatment.
The study also reminds us to avoid overreliance on p16 alone when deciding disease biology. In oropharyngeal cancer, HPV positivity often has stronger prognostic meaning. In oral cavity cancer, the situation is less clear. The paper suggests that HPV may be a cofactor in some cases rather than the only cause. This means treatment decisions should be guided by the overall clinical picture, not just one marker.
Prevention:
Prevention begins with stopping tobacco use. This is the single most important measure. Smoking, chewing tobacco, and betel nut use should be avoided. These habits are strongly linked to oral squamous cell carcinoma in India. Prevention efforts should focus on both community education and individual counselling. A person who stops tobacco use lowers future cancer risk and improves general health (Singh MP et al, 2018).
Regular oral examination is another major preventive step. People with tobacco habits should have routine mouth checks. A non-healing ulcer, a white patch, a red patch, or a persistent lump should be examined early. The study shows that the oral cavity is accessible, so screening can be effective if it is done on time. Early biopsy of a suspicious lesion can prevent delay in diagnosis.
Good oral hygiene also matters. Frequent cleaning of the teeth and mouth reduces irritation and infection. A balanced diet is useful as well. The paper notes that poor oral hygiene and low micronutrients may act as cofactors in cancer development. That means nutritional support may help reduce overall risk, even if it cannot prevent every case by itself. Healthy food habits also support healing and general well-being.
HPV prevention is also relevant. HPV may play a role in a subgroup of oral squamous cell carcinoma. Safe sexual practices can help reduce transmission. HPV vaccination may also lower infection with high-risk HPV types. The study found HPV-16 and HPV-18 in a notable number of p16-positive cases. That supports the idea that HPV prevention remains worthwhile in oral cancer control.
Awareness is essential because symptoms may seem minor at first. Many patients wait too long before seeking help. Education should teach people that a mouth ulcer lasting more than two weeks is not normal. Any lesion that bleeds, enlarges, or causes swallowing trouble should be checked without delay. Early action can improve the chance of cure.
Prevention also depends on the health system. Dental clinics, primary care centres, and ENT services can all help with screening. High-risk groups should be identified early. Tobacco users, betel nut users, and people with poor oral hygiene need more attention. In busy settings, a simple mouth inspection can make a real difference. The earlier a lesion is detected, the better the outcome.
The study ultimately shows that oral squamous cell carcinoma is not a single-disease problem. It has strong lifestyle links, possible viral links, and clear late-stage consequences. Tobacco control remains the foundation of prevention. HPV control, screening, oral hygiene, and patient education strengthen that foundation. Together, these measures can reduce the burden of a cancer that is common, serious, and often preventable (Coelho KR, 2012; Singh MP et al, 2016).
Author:
Dr. Farhat Naz, Ph.D., Department of Pathology (Nanomedicine), All India Institute Of Medical Sciences (AIIMS), New Delhi, India.
References:
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