Oral+Squamous+Cell+Carcinoma

=The Cancer=

Mr. Wong is a 64 year old, Chinese American man living in Honolulu, Hawaii. He lives with his wife in the valley of Manoa, two blocks from his oldest daughter and two grandchildren. Every day, Mr. Wong goes into the work at the Chevron service station that he manages on East Manoa Road. However, he takes Wednesdays off to golf with his long time friend from college. Mr. Wong is 5’8”, 150 pounds, and was an avid smoker in his youth, but recently has cut back to one or two smokes a day. He also has a history of diabetes and hypertension. About one month ago, Mr. Wong developed what he thought was a cold sore on the right side of his tongue. The last time he went to the dentist was 3 years ago, but he recently scheduled an appointment after the cold sore didn’t seem to heal right. The dentist examined the lesion and became suspicious, so she took a biopsy that came back positive for oral squamous cell carcinoma. She wrote Mr. Wong a referral to an oncologist so he could get a better look.

Oral squamous cell carcinoma (OSCC) is the most common type of cancer that occurs in the mouth. The cancer begins when squamous cells that make up the lining of the oral cavity undergo uncontrolled proliferation and develop into tumors. The general term, oral cancer, refers to the area between the vermilion border of the lips and the back third of the tongue, which is also characterized by the junction of the hard and soft palates. On the other hand, oropharyngeal cancers affect the back of the mouth, including the tonsils and soft palate. OSCC affects about 30,000 people in the United States each year. This type of cancer constitutes about 3% of cancers in men and 2% in women, and usually occurs at or after the age of 50. About 40% of OSCC cases start on the tongue, and 38% occur on the lower lip. The five-year survival rate of this cancer is greater than 50%, but early detection is key.

There are several risk factors for developing OSSC. They include: gender, tobacco use, alcohol, HPV, and genetics, although those with known genetic mutations like fanconi anemia and dyskeratosis congenita (forms of bone marrow failure that in turn affect the blood) develop oral cancers at an earlier age. Individuals with these known genetic mutations usually develop OSCC earlier because mutations are already present in the DNA, so their cells do not take as much time to acquire the necessary mutations to become cancerous. OSCC commonly affects more men than women. The gender disparity may be due to higher levels of tobacco and alcohol use in men compared to women. Mr. Wong’s history of smoking in his youth probably increased his risk for OSCC. In addition, Mr. Wong skipped multiple dental appointments because he maintains relatively good oral hygiene and didn’t feel the need to go. In its early stages, OSCC can be asymptomatic or appear as small, white or red patches on the gums, tongue, and lining of the mouth. However, when the cancer progresses, it can cause more noticeable symptoms such as difficulty chewing or swallowing, numbness, pain, and persistent bad breath. Many instances of OSCC can be diagnosed at early stages with routine dental care, but many people skip out on these appointments due to cost or lack of noticeable symptoms.

As in all cancers, OSCC is categorized into stages. Stage 0, also referred to as carcinoma in situ, is when abnormal cells are growing only in the epithelium. The cancer has not yet spread to deeper tissues or other locations. Stage I cancer is characterized by a tumor that is no more than two centimeters across and has not yet spread to other structures of lymph nodes. Stage II is when the tumor is 2-4 centimeters but has not spread to the lymph nodes. The cancer is considered stage III if the tumor is larger than four centimeters or a tumor of any size has spread to one lymph node. The last stage, stage IV cancer, is divided into three subsections. Stage IVA is when the tumor invades nearby structures, but may or may not have spread to the lymph nodes. Stage IVB is when the tumor has invaded deeper tissues and may have invaded lymph nodes and metastasized. Stage IVC is when the cancer has spread to other parts of the body, most commonly the lungs.

Mr. Wong was diagnosed with stage III oral squamous cell carcinoma. OSCC is one of the more aggressive forms of oral cancer as the tumors grow faster than other oral cancers such as verrucous carcinomas. In Mr. Wong’s case, the cancer is considered stage III because the tumor is larger than four centimeters, and currently makes up almost one third of his tongue. Nevertheless, Mr. Wong is fortunate in that the cancer has not yet metastasized. If the tumor on the tongue is localized, the 5-year survival rate is over 75%. However, if the cancer spreads to the lymph nodes, the survival rate is cut in half. Furthermore, people with oral cancers are at an increased risk of developing a second cancer in the head or neck. The oncologist predicts that, with the right treatment, Mr. Wong will make a full recovery, however he should start treatment soon to avoid further progression of the cancer. Mr. Wong is in denial and does not understand how his cold sore could be cancerous, so the oncologist referred him to a molecular biologist for a better explanation of his condition.

=**The Epigenetic Basis**=

Many oral squamous cell carcinomas are the result of DNA mutations caused by epigenetic and genetic factors. Smoking is the number one risk factor for OSCC, and has been linked to about 75% of cases. Smoking causes cancer because many of the chemicals found in cigarette smoke can bind to and damage DNA. If the lesions are not repaired a mutation could arise, and the accumulation of mutations in genes that confer a growth advantage to the cell can result in cancer. However, smoking can cause epigenetic changes within cells as well, though the specific mechanisms are still unclear. An epigenetic change is one that affects gene expression without changing the DNA. For example, CpG islands are hypermethylated in OSCC as compared to normal tissue. Hypermethylation is the state where several cytosine residues, each adjoined to a guanine just downstream, are modified by the addition of a methyl group on the base. CpG islands are short sequences of DNA located at or near promoters. When these sites are hypermethylated, the chromatin structure changes to inhibit the transcription of the specific gene. Each individual case of OSCC is different, but one commonly inhibited gene is p16INK4A.

The protein p16 is a known tumor suppressor whose function is lost in 83% of oral cancers. p16 inhibits cyclin-dependent kinase 4 and 6 (CDK4/6). CDK4/6 are important components of the cell cycle that bind with cyclin D to phosphorylate the retinoblastoma protein (Rb). When Rb is not phosphorylated, it binds and inhibits E2F, a transcription factor for genes needed later in the cell cycle. On the other hand, hyperphosphorylated Rb dissociates from E2F, which can now activate transcription. Therefore, by inhibiting the D-CDK4/6 complex, p16 has the capacity to arrest the cell cycle in G1 and prevent progression into S phase. However in cancer cells, with a hypermethylated CpG island at the p16 promoter, no transcription of p16 occurs. With the loss of p16, the cell can no longer inhibit the phosphorylation of Rb, thus the cell cycle continues despite potential signals not to. This can lead to uncontrolled proliferation, one of the major hallmarks of cancer.

The hypermethylation of the p16 CpG island occurs early in OSCC progression in both tumors and precancerous lesions. A study done by Peter van der Riet //et al//. (1994) analyzed both OSCC tumors and preinvasive lesions for the inactivation of p16. They found the frequency of inactivation in p16 to be 72% and 71% respectively. The similarity in frequency between tumors and preinvasive lesions thus suggests that p16 becomes inactive early in tumor development. Additionally, hypermethylation and the subsequent inhibition of the p16 CpG island has also been associated with an earlier start of smoking. As shown in Table 3 from M. Hasegawa //et al//. the odds ratio of having p16 promoter methylation increases as the starting age of smoking decreases. Specifically, individuals who started smoking before the age of 17 have 4.3 times higher odds of p16 promoter methylation compared to those who started after the age of 20. The association between starting age of smoking and odds of p16 hypermethylation suggests that smoking does have an epigenetic effect on DNA.

Contrary to expectations, the hypermethylation of the p16 CpG island has shown an inverse relationship to lymph node metastasis. M. Hasegawa //et al//. found that as the number of lymph nodes involved increased, the odds of p16 hypermethylation decreased. Those with 2-3 nearby lymph nodes affected had 0.1 times the odds of p16 hypermethylation compared to those with no nearby affected lymph nodes. The decreased lymph node involvement associated with p16 hypermethylation means that the risk of metastasis to other organs is decreased as well. Furthermore, in OSCCs that do not metastasize, the efficacy of treatments like surgery improves, and the patient’s survival rate is increased by 2-fold. It is unclear why p16 hypermethylation is associated with decreased metastasis, however it may be because the mutation is epigenetic rather than genetic. Therefore, the cells don’t contain the necessary gene mutations to facilitate effective metastasis that is not easily detected by the immune system.

With a newfound understanding of what is going on and how his cancer developed, Mr. Wong schedules another appointment with his oncologist to review his treatment options. Targeted therapies to slow the growth may be effective in his case, especially since his oncologist would want to avoid metastasis and further growth to preserve what is left of Mr. Wong's tongue. However, targeted therapies alone will not do Mr. Wong much good since his cancer is already stage III. In addition to targeted therapies, Mr. Wong will likely require a more radical and standard form of treatment for his cancer.

=Treatment=

Oral squamous cell carcinomas are usually detected when the patient develops noticeable symptoms such as white or red patches on the tongue or gum. Therefore, there is no special screening process for OSCC, however individuals should attend routine dental exams. Semi-annual dental exams help to protect and promote good oral hygiene; they also detect OSCC in patients with no painful or obvious symptoms.

 Since Mr. Wong’s cancer has grown so large, the current standard of care is a hemiglossectomy – the removal of half the tongue – followed by chemoradiation therapy.Once the tumor is removed, the border is examined for clean margins to ensure the entire tumor is gone. During the same procedure, the surgeon will also perform a Frankenstein-like reconstruction of the tongue. The tongue is essentially one big muscle, so in order to reconstruct the tongue, the surgeon will need to obtain a piece of muscle that most closely matches the resected tissue. Although the body is full of muscle, tissue for this reconstruction is usually taken from the forearm or the inner thigh because the vasculature and type of muscle are the most similar to that of the tongue. The muscle from the arm or leg is excised, adjusted for size and shape, and then sewn directly to the tongue resulting in a patchwork of muscle that will eventually fuse and function like the original tongue.  An advantage to performing the reconstruction with tissue from another part of the body is the ability to select tissue that most closely matches the portions of the tongue that are removed in terms of vasculature and size. Another advantage is that the reconstructive tissue has not been exposed to any neoadjuvant locoregional radiation therapy, so it has an increased healing potential. Although studies have shown that there is no significant difference in function between reconstruction using the arm and thigh, the arm muscle may be the better option in Mr. Wong’s case as it is thinner and requires less debulking before implantation. However, a downside to using muscle from the arm is that the scar on the forearm is more noticeable than a scar on the thigh. However, Mr. Wong is not terribly concerned with the cosmetics of his forearm, so this will not be a problem.

 The tongue is a critical component in talking as well as eating. Therefore, following surgery, Mr. Wong will need extensive speech and swallowing therapy to help restore motor function to the tongue. Since the muscle in the arm or leg has no taste buds, Mr. Wong will no longer be able to taste with half his tongue. However, after speech and swallowing therapy, that will likely be the only obvious, long-lasting impairment from the operation.

 In addition to therapy for his tongue, Mr. Wong will undergo adjuvant chemoradiation therapy to decrease the risk of recurrence. Cisplatin is the most common drug used in cases like Mr. Wong’s. It is considered an alkylating agent that induces apoptosis in cells by crosslinking the DNA. Adjuvant therapy is especially important in Mr. Wong’s case because his cancer is so far advanced, and there is a high probability of metastasized cells else where in his body even if no secondary tumors have developed yet. Mr. Wong will receive daily locoregional radiation five times a week concurrent with 100 mg/m2 of Cisplatin intravenously for six weeks. Common side effects of chemotherapy include nausea, vomiting, hair loss, and loss of appetite. Cisplatin in particular has been shown to cause kidney and nerve damage. However, most of these symptoms will subside once treatment ends. Even with adjuvant chemotherapy, the rate of recurrence is 10-26% depending of the stage of the tumor. Based on this, a study in the Journal of Cranio-Maxillofacial Surgery recommends follow-ups every six weeks for the first six months after surgery and every three months during the second six months. By the third year, follow-ups can be semi-annual, depending on the discretion of the doctor. Recurrence of OSCC is more common in more advanced cancers and should the cancer return, the five-year survival rate is low, at just 15-35%.

 There are a few clinical trials with targeted therapies for OSCC. One in particular may be especially well suited for Mr. Wong’s case. The clinical trial, located at the Emory University Winship Cancer Institute, focuses on the prevention of recurrence after surgery using soy isoflavones. Isoflavones are soy-derived compounds such as genistein that have been shown to have anti-tumor effects with minimal toxicity to normal tissue.   Isoflavones have mainly been studied in breast cancer where they inhibit the estrogen receptors, however they have also been shown to inhibit other pathways such as the Akt pathway that is important in cell survival. A study, by Ming Zhu Fang et al., showed genistein inhibited cell growth by up to 90% (Figure 2). The study also observed reactivation of previously hypermethylated p16 as a result of treatment with genistein, though they stated that further research is needed to analyze the exact mechanism.

 Therefore, this particular clinical trial may be good for Mr. Wong because it focuses on the change in p16 methylation, one of the prominent mutations found in his cancer, and tumor recurrence as a result of the isoflavones. Additionally, since Mr. Wong’s risk of recurrence is elevated because his cancer is stage III, this clinical trial may help to delay or prevent recurrence and ultimately increase his chances of overall survival. If Mr. Wong chooses to participate in this study, he would orally take soy isoflavones for 14 days prior to receiving surgery to resect the tumor. This trial would not change Mr. Wong’s post-operation care, and he would receive the chemoradiation therapy regardless of his participation in this trial. One downside of this study is that since the it is only offered in Georgia and Michigan, Mr. Wong would need to commit to traveling there for initial treatment and several follow ups. However, since the isoflavones are administered prior to surgery, the time commitment for traveling is less than if he was receiving an adjuvant chemotherapy treatment that needed to be administered for an extended period of time after surgery.

 This particular clinical trial is still ongoing, and results are not available yet, however it looks well suited for Mr. Wong. I recommend that Mr. Wong participate in this trial because it is the only one targeted at p16 methylation that he is eligible for. Additionally, soy isoflavones have been shown to be minimally harmful to normal tissues, which may result in fewer side effects. Since Mr. Wong will definitely need the hemiglossectomy, the goal after surgery would be to prevent recurrence, which is the main focus of the study. Should Mr. Wong agree to participate in this trial, he can start treatment as soon as possible.

=Aperçu =

It seems that a lifetime of smoking has caught up to Mr. Wong. Although his post-surgery prognosis looks relatively good, he will need extensive speech and swallowing therapy to regain function of his tongue. Even after all that, there is still a risk of recurrence or development of cancer somewhere else in his body, particularly in the lungs. Since we know that smoking likely played a role in the development of his cancer, it is hard not to look back and ask if, in the end, the smoking was worth sacrificing his health.