Missing the woods for the trees

In India, the oral cavity is one of the most abused areas of the body. Tobacco either smoked or smokeless has caused a huge amount of damage to a whole generation of people especially men. In India, 90 to 95% of oral cancers are Oral Squamous Cell Carcinoma (OSCC). The international agency for research on cancer has predicted that the incidence of cancer in India will increase from 1 million in 2012 to more than 1.7 million by 2035. They also indicate that the death rate because of cancer will also increase from 680000 to 1- 2,000,000 in the same period. In India, 20 people out of 1, 00000 population are affected by oral cancer which accounts for 30% of all cancers in India. To put it in another way five people in India die per hour due to oral cancer. The last decade has seen new strides being made in the fields of diagnostics, imaging, molecular biology, and surgical techniques. In spite of these multiple advances, the five-year survival rate remains stuck at 50%. Effectively this means that one in two people suffering from OSCC does not live for more than five years after treatment. The reason for this abysmal survival rate is manifold. Late diagnosis, difficulty in access to healthcare, and financial difficulties all contribute to the poor survival rate. However, all these factors come into play with malignancies of the other parts of the body too. The number of hurdles in the path of early diagnosis remains the same and so do the limitations when it comes to access to treatment. However, the last decade has seen definite improvements in the five-year survival rate of most malignancies especially those which occur in easy-to-identify locations that are cervical, breast, skin, etc., The 5-year survival for these malignancies ranges from 60-80% which is much more than that seen with OSCC. These statistics are difficult to explain just on the basis of local factors. We need to look further than the obvious so as to arrive at any sort of conclusion with regard to what differentiates oral malignancies from other malignancies. The malignancy of the oral cavity affects all its parts. Malignancies can develop in the lining mucosa, masticatory mucosa, or specialized mucosa. It may occur either on the keratinized mucosa, non-keratinized mucosa, or para-keratinized mucosa. The classical surgical treatment protocols treat them all in an identical manner irrespective of their site. This one-cap-fits-all-heads approach is probably counterproductive. Over a period of time with experience, clinicians have come to realize that malignancies arising from different parts of the oral cavity behave differently especially the tongue.[¹] The biological behavior of OSCC of different parts of the oral mucosa differs in many aspects. Malignancies of the tongue tend to be more aggressive, and have more vascularity and their prognosis depends on the depth of invasion predominantly, whereas malignancies of the buccal mucosa tend to have a better prognosis and metastasis is dependent on the degree of differentiation. Studies have proven the differences in the expression of molecular markers at these two sites. Experimental oral carcinogenic studies have reported site-specific differences in the biology of oral carcinogenesis. Furthermore, studies have observed the molecular markers expressed tend to be distinct when compared. In comparison of buccal and tongue carcinoma p16 and p21 expressions are significantly different. Downregulation of p16 and p21 is found to be significantly high in tongue carcinoma. Prognostically, p53, p16, and cyclin D1 expressions are important for predicting prognosis in buccal carcinoma,[²] whereas none of these biomarkers are of prognostic significance for tongue carcinoma. These findings could further indicate that oral cancer of different anatomic sub-sites is characterized by alterations in different pathways. This may also, to a certain extent explain the difference in the clinical outcomes between the tongue and buccal mucosa. The other factor in favor of this premise would be the fact that most buccal mucosa malignancies tend to be associated with tobacco whereas tongue malignancies are often seen in patients without this habit. For the same size of tumor, tongue malignancies tend to be more aggressive, occur at a younger age, and are more likely to occur in women. All these factors have been evaluated and taken cognizance of by various investigators and there is an increase in the number of takers for the premise that these malignancies differ significantly. There is another difference that has not been taken cognizance to date. If we revisit the steps in the development of the oral cavity we will recollect that epithelium is derived from all the germ layers the ectoderm, endoderm, and mesoderm. In the oral cavity, parts of the oral cavity are lined by epithelium derived from the ectoderm and partly from the endoderm. The tongue is derived from epithelium arising predominantly from the endoderm whereas much of the lining mucosa comes from epithelium derived from the ectoderm. That these tissues are developmentally different may contribute to the distinct clinical behavior of tumors developing from them. As we are all aware tumors tend to dedifferentiate as they become more aggressive. Hence poorly differentiated tongue malignancies will reflect the properties of the primitive endoderm. These will be distinct from the buccal mucosa malignancy, which may reflect properties of the primitive ectoderm. This may be the basis of the difference in behavior of these malignancies. So are we missing the obvious difference? Hence, the title 'missing the woods for the trees'. In continuation of this hypothesis of distinct germ layer origin, these malignancies warrant separate protocols for their management. These customized treatment protocols taking into consideration the origin of the lining epithelium and tailoring chemotherapeutic regimes accordingly may result in better survival rates for patients with Oral Squamous Cell Carcinoma in the future.