Oropharyngeal Carcinoma: Younger Patients and Less Smoking
Gabe Calzada, M.D.
May 11, 2006

Oropharyngeal cancer is definitely a multidisciplinary problem. Treatment is guided not only by trying to obtain a disease-free survival, but also trying to preserve function in these therapeutic outcomes. Overall survival rates over the past 30 years have not changed, and patients succumb to their disease due to either distant metastases or second primary lesions. Epidemiology is a relatively uncommon cancer. It is only seen in about 1% of all new cancers in the US. It has been estimated that in one year, there are approximately 9,000 cases reported here in the United States and approximately 2,000 deaths due to this type of cancer. Traditionally, the peak incidence has been in the sixth and seventh decades of life, and there has been a distinct male predominance. In addition, I have performed some research that shows different trends with regards to those epidemiologic trends. As with other head and neck cancers, the most important etiologic factor continues to be prolonged exposure to tobacco and alcohol. These prolonged exposures to carcinogens leads to field cancerization or a condemned mucosa. These carcinogens cause molecular changes to all mucosa of the head and neck areas, leading to high susceptibility to second primary lesions. Along with the two other main residents, I reviewed all patients presenting to MD Anderson with previously untreated oropharyngeal carcinoma. We reviewed over 4,000 charts of patients at MD Anderson. Statistics are currently pending. Initial data is interesting, in that the patient population is significantly getting younger and younger. In addition to this, the data shows that there is less tobacco burden in these patients. Basically, these are younger patients with less tobacco smoking issues. In the 1950s, the mean age was 63 years of age. By the year 2000, the mean age dropped down to low 50s. in the 1950s, only about 2% of these patients were under the age of 40. In the year 2000, we are seeing a higher percentage, with up to 6% being younger than age 40.

What possible causes account for this trend of younger patients and less tobacco usage? There has been discussion with regards to human papilloma virus and the etiology of oropharyngeal cancer. This is very interesting because HPV is an infectious disease, and an infectious disease causing cancer is definitely a topic worth a lot of basic science review. Overall prevalence of human papilloma virus in head and neck has been reported to be around 20%-25%. In particular, there is a higher prevalence in oropharyngeal carcinoma, up to 57%. There are about 100 strains, and human papilloma virus strain 16 is most commonly associated with head and neck cancer. Research has shown that if human papilloma virus is positive with these cancers, there tends to be a better prognosis and less tobacco history. If you review the CDC government web site, you will see that the incidence of human papilloma virus is actually quite high. In sexually active adults, approximately 50% of men and women are infected with a strain of human papilloma virus. Also, statistics show that, by the age of 50, approximately 80% of women have an infection of human papilloma virus. There are no diagnostic techniques and really no treatments at this time.

With regard to oropharyngeal physiology, the oropharynx is very important for speech, swallowing, and respiration. It requires complex neuromuscular coordination, and any manipulation of these tissues with oncologic surgery can have devastating effects. It can affect speech, and result in uvulopharyngeal insufficiency, aspiration, and dysphasia.

Typically, the histology in this area is mucous membrane-lined mucosa, nonkeratinized, stratified squamous epithelium with underlying connective tissue, with mixed salivary glands to help moisten the area. The oropharynx has, as well, fewer premalignant lesions than in the oral cavity. All our studies of human papilloma virus come from cervical cancer, and we have noted that the virus tends to invade the basal layers. This is also similar to the layers of the mucosa along the tonsil and base of tongue. It will be interesting to see what the molecular mechanism of human papilloma virus is and why it has a predominance for this type of mucosa in the oropharynx.

Oropharyngeal Pathology: Overwhelmingly, the pathology in this area is squamous cell carcinoma. Over 90% of the tumors arising here are squamous cell in origin. Other tumors include verrucous carcinoma, which does not necessarily metastasize and spread superficially. On contrary, we have lymphoepitheliomas. These have a high cell turnover rate. They are a variant of poorly differentiated squamous cell carcinoma, and have a predominance to spread to the neck early. Other tumors include adenoid squamous tumors, lymphomas, minor salivary gland tumors and, very rarely, mucosal melanomas and sarcomas.

The key to diagnosis is a thorough history and physical exam. These patients tend to present with advanced disease. They usually present with pain and dysphagia as the most common complaints. The key is a systematic physical exam with visualization of all mucosal surfaces. The field cancerization theory again states that if you have one lesion then you may have a second primary lesion. The importance of digital palpation, especially in the base of the tongue area, cannot be over stressed, as this helps elicit any solid masses there that are tender.

Diagnostic Evaluation: Each of these patients should have a confirmed diagnosis either by a biopsy of the primary site or FNA of the neck disease. Imaging includes preoperative chest x-ray to evaluate for pulmonary metastases and CT of the neck to evaluate for extended regional metastases to the neck. Labs include a CBC and liver function tests. Surgical endoscopy cannot be overstated with regards to looking for a second primary, as this can be as high as 8%.

The staging of oropharyngeal carcinoma is based on the American Joint Committee of Cancer. They use the TNM classifications. With regards to T size, T1 lesions are 2cm or less, T2 are 2cm to 4cm, T3 is greater than 4cm, and T4 invades adjacent tissue, such as bone or muscle soft tissue. Staging is shown here to the left. Stage IV can be divided up into A, B, and C as well. B is N2 disease, and C is N3 disease. This has implications with regards to prognosis.

So, how do these patients present? Shah reviewed the literature and saw that the majority of the patients are presenting with stage II and higher disease, as well as a high percentage showing nodal metastases. Again, lymphatic metastasis is quite common. Generally, these types of cancers metastasize to levels II-IV with levels I and V being secondary stations. Lymphatic drainage is often bilateral. Occult metastases in an N0 neck can be seen in as high as 20%, and bone involvement can been seen in around 17% of these lesions.

The oropharynx is really divided up into four major subsites: the tonsil, base of tongue, soft palate, and pharyngeal wall. The vast majority of these cancers present in the base of tongue as well as tonsil, and approximately 25% are on the soft palate or the pharyngeal wall.

Moving on to the oropharyngeal anatomy, the nerves to this area can give us big insights into these tumors. The sensory nerves include the glossopharyngeal and vagus nerves. Motor nerves in this area include the hypoglossal, and referred pain through Jacobson's nerve can give us clues to referred pain to the ear. Invasion of these tumors into parapharyngeal spaces or the retropharyngeal spaces can lead to cranial nerve involvements IX- XII and acts as conduit to spread to the skull base. Tonsil cancers can invade the masticator space and lead to trigeminal nerve involvement, especially in the V3 area, which can lead to pain and trismus. These can all give us insight on pathology in this area.

In the base of tongue, these tumors tend to be very highly invasive and present with advanced disease. It is a tough area to examine and the base of tongue already has lymphatic nodularity, and usually these tumors spread anteriorly to involve the root of the tongue. We can get insight into this if the patient has difficulty with tongue protrusion. Spread can also be lateral along the tonsils or down the pharynx. With regard to metastases from the base of tongue, the lymphatics are quite plentiful in this area and bilateral spread is present about 30% of the time. You will see these neck metastases to levels II and IV most frequently, again bilateral.

Moving on to the tonsil or tonsillar area, most often these cancers present along the anterior tonsillar pillar. As pictured here, these tumors can frequently be exophytic, spread anterolaterally, and can often extend to the base of the tongue. Pictured here on the top left, you see how close the tonsil is to the pterygoid musculature as well as the parapharyngeal space and, again, leading to that conduit to the skull base. Primary lymphatic drainage to these tonsillar areas is mainly level II. Again, literature shows that even different areas of the tonsil metastasize differently. Tumors along the anterior tonsillar pillar have less frequent metastasis than tonsil cancer that is mainly in the tonsillar fossa. Also, it has been noted that in tonsil cancer presenting with posterior tonsillar pillars, the spinal accessory nodes should be looked at, as well as the posterior triangle.

With tumors of the pharyngeal wall, like most of these tumors, present with advanced disease. Pharyngeal wall is less nodular than the base of tongue. You can more readily appreciate these tumors than those at the base of tongue. Again, these present with pain and neck lymphadenopathy. They may spread superficially to the nasopharynx or inferiorly to the hypopharynx. Metastases from these pharyngeal wall tumors are again in the levels II-IV and often are bilateral. Particular attention must be paid in this type of cancer because they can often spread to the retropharyngeal lymph nodes. A Japanese surgeon, Hasegawa, noted high prevalence if his patients had positive retropharyngeal lymph nodes from this area.

With regards to the soft palate, you can see that the soft palate tumors generally present on the inferior surface of the soft palate and can spread in a centrifugal fashion. Primary lymphatic drainage again, like most of these tumors, is to level II; and with soft palate tumor, the occult metastases occur about 10% of the time, and bilateral metastases about 15% of that time. Distant metastasis is a major issue especially when the disease is later in its course. It is quite rare on presentation. It occurs in only 2%-5% of initial presentation. Most common sites, as pictured here, are some pulmonary metastases and, in addition, it can spread to liver as well as bone.

Overall Management: The management to this oropharyngeal cancer is definitely a multidisciplinary team approach. It involves a head and neck oncologist, a reconstructive surgeon, medical oncologist, radiation oncologist, as well as a prosthodontist, and speech pathologist. Each of these people play key roles in the decisions made for management. Surgery and radiation, either alone or in combination, have been the mainstay of oropharyngeal carcinoma for many years. If you review the literature, there are many proponents of having surgery as the primary treatment modality, and other proponents who say radiation should be the way to go.

There are several factors affecting the treatment choice. You must consider the tumor and how big it is. Consider the patient’s desires, social situation, and how difficult it is for the patient to come for treatments. Overall management is really balanced between preserving functional outcomes versus long-term disease-free survival.

Radiotherapy has been shown to yield better functional outcomes in similar local regional control. In 2001, Parsons and a group from the University of Florida reviewed the medical literature and performed a meta-analysis of the literature. They reviewed the literature from 1970 to 2000, looking at radiation therapy versus surgical therapy as the primary treatment modality. They found that local regional control and overall survival at five years was similar for either radiation or surgery. But, for the most part, they found statistical significance with regards to a higher complication rate, in particular a fatal complication rate, of patients treated with aggressive surgery. In addition, quality of life is better with radiation therapy. Based on this meta-analysis, their overall recommendation is that oropharyngeal cancers be treated with radiation therapy. Let us go ahead and break it down with regards to each, and let us see what the proponents are.

Management of the primary tumor with surgery: On a positive note, it avoids the long-term affects of radiation therapy, such as xerostomia. In younger patients, these can get second malignancies long term. Also, surgery is a treatment with a shorter duration, with standard radiation protocols calling for once a day treatment for six to seven weeks.

Why would you argue against surgery? Even these small lesions metastasize early and often metastasize bilaterally. So, if you treat with the surgical indication to the primary tumor, you are metastases to the neck can be missed. In addition, surgical treatment fails to address some retropharyngeal nodes, which are usually addressed with radiation therapy. The metastases to the neck require bilateral neck dissections, which is associated with some morbidity. Lastly, when you perform surgery on these patients, you often find pathologic features that require radiation therapy, such as if the primary tumor has close margins, is large or thick, exophytic, and hard to get around. In the neck, you will often find multiple nodes and extracapsular extension. Based on these pathologic factors, you are going to provide the patient with radiation therapy as well. The logic is, if you are going to provide them with radiation therapy and if you have equivalent outcomes, people would argue you should treat with radiation therapy first.

What are the arguments for primary tumor treatment with radiation therapy? Conventional radiation therapy is given 60-70 Gy over six to seven weeks. When you review the literature, the majority comes out of the University of Florida - they are strong proponents of radiation therapy. Fein, in 1996, reviewed their outcomes. He reviewed 490 patients treated with primary radiation therapy. At two-year outcomes, the local control rate was 73% and five-year survival was 77%, which is actually very good, especially when compared to surgery.

As technology advances, there are new modalities being developed. These include intensity modulated radiation therapy (IMRT). The goal of the IMRT is to provide higher Gy to the primary sites, but avoid the salivary tissue. This has been shown by Narayan, in 2005, who reviewed the literature about IMRT, and found less complications with regards to targeting salivary tissue and a better control rate. The IMRT is still in the development stage involving three-dimensional models and complex algorithms. The radiation therapist has to work closely with the surgical oncologist, because they have to target and differentiate pathologic disease and normal tissue. The goal is to preserve the normal tissue function.

What does the literature say with regard to the neck? N1 or N0 necks are usually treated with a single modality, either radiation therapy or neck dissections. Proponents of the neck dissections say that it can give some pathologic staging. N2 and N3 disease or advanced neck disease is usually recommended by combined modality. Reddy, in 2005, advocated from Johns Hopkins. He looked at patients with primary and advanced neck disease. He advocated performing a neck dissection, seeing what the pathology showed, and deciding whether or not postoperative radiation therapy is needed. He quoted a three-year survival of 100%. The limitation in his study is that he only looked at 16 patients. Again, you have to treat both necks, which will require bilateral neck dissections, or just treating both necks with radiation therapy. Again, as previously mentioned, the Japanese surgeon Hasegawa, in 1994, showed that a significant proportion, up to 30%-50%, of patients can have that retropharyngeal node presentation. This is not necessarily addressed with standard neck dissection, but it is with radiation therapy.

How do we treat patients with advanced disease? Tupchong, in 1991, surveyed patients with advanced disease, stages III and IV. He looked at surgery and postoperative radiation therapy. He noted overall survival rates to be 30%-40%. He noted that recurrence rates are most often local regional as opposed to systemic. He also noted that, with surgery, there is significant morbidity associated with swallowing, speech, and cosmesis. So we have a low survival rate and high morbidity.

Based on this, new protocols with regard to chemoradiation are coming out. These chemoradiations aim to improve survival rates to greater than 40%, and to try to minimize morbidity. If you read the literature, there are currently many chemoradiation clinical trials underway. There are really two main combinations of chemoradiation therapy: induction chemotherapy as well as concomitant or concurrent chemoradiation therapy.

In induction chemotherapy, initial chemotherapy is followed, after the chemotherapy, by radiation therapy. There have been several trials, and they show that induction chemotherapy is active against inducing disease remission in up to 80%-90%. But the randomized trials have failed to demonstrate a clear importance of induction chemotherapy on local control and overall survival. Trials of induction chemotherapy are continuing but this is by no means the standard of care, because, again, what we are trying to improve is overall survival and it has not been shown that induction chemotherapy helps with this.

With concurrent chemotherapy, chemotherapy is given during radiation therapy. The theory is that this provides potential for better regional control and better control of distant metastasis. This combination has also been shown to enhance the cytotoxicity of the radiation therapy given. The disadvantage of giving concurrent chemotherapy is that there is increased toxicity, both locally and systemic, especially with things like dry mouth. There have been several studies in the literature, particularly four or five good studies, that showed overall survival with concomitant chemoradiations is greater than 50%, thus beating the goal standard of 30%-40%. Several of these trials do not specifically address oropharyngeal cancer. They are lumped in with other types of cancers, such as laryngeal cancer, and they are just arriving at oropharyngeal cancer data. Calais, from Hopkins, is the only one in the literature that I found who looked at concurrent chemotherapy only for oropharyngeal cancers. This study looked at 226 patients. He divided his arms into the radiation arm or arm "A" verus radiation with current chemotherapy. The way he set up the study is six weeks of once‑daily radiation therapy in addition to three cycles of chemotherapy, which include carboplatin and 5-FU. These three cycles were four days of each. Based on these two arms, he found that local regional control was much higher when he added the chemotherapy, 66% versus 47%. In addition, he noted that overall survival was improved with over 51% survival at five years versus 31% with just radiation alone. So, these studies show that the future really is coming with regards to chemoradiation and getting better cytotoxic drugs as well as modulating the radiation therapy.

Salvage Surgery: We are seeing more and more salvage surgery these days because the treatment modality is really shifting to chemoradiation. The goals of the surgery are different. If the patient fails radiation therapy, usually they are presenting with advanced disease, and the surgery we were performing has a success rate of less than 15% for this advanced pathology. The goals of our salvage surgery these days are really to help control, more of a palliative function, with regards to helping control pain as well as fistulas and what not. With regard to the salvage surgery to the primary site, there have been several ways to approach these tumors. You can approach through a transoral approach, through the mouth. This is really seen with up and coming technology, and includes laser transoral or laser excisions. You can go through the mandible. Pictured here is a mandibular split; splitting the tongue to get to the pharynx as well as doing mandibular swing, such as pictured here to the left, to get to the base of tongue. Lastly, you can go transpharyngeal, either suprahyoid or through to the lateral neck to approach these tumors, pictured here to the bottom left. As you can see, these procedures can be quite morbid and difficult for the patient to tolerate.

Another thing that we are seeing is salvage surgery for residual neck disease. As we treat more and more these patients with chemoradiation, you are going to see some patients with complete response. With follow-up for some patients, you are going to notice some matting of the neck or some findings on follow-up CT scans. What do we do with regards to that? In 2001 Gary Clayman really published the definitive argument paper with regards to residual neck disease after chemoradiation. His recommendations are that neck dissections should be performed six to ten weeks after completion of radiation therapy; and he stated that we need to really address levels I-V. He reached this conclusion by looking at 66 patients treated with chemoradiation. These 66 patients were divided into two groups. One, the patients that had complete response, versus the second group that had no response or a partial response. His data showed that there is a statistical significance in that the people who had complete response had better local control and overall survival. Now, taking the B arm of the study, the patients that had no response or partial response, he performed neck dissection on one group and no neck dissections on the other group. He showed that survival as well as local regional control was better in the group who had neck dissection. Based on this study, if there was complete response after chemoradiation, no further surgery is needed on the neck. Neck dissection was recommended for those that are treated with chemoradiation and have residual neck disease.

Reconstruction of these surgical defects is really tailored to the size of the defect. If it is a small defect, you can close with primary closure. With a medium size defect, you can do mucosal advancement flaps and palatal flaps. These larger defects are now being revolutionized by microvascular reconstruction. Microvascular reconstruction has really flowered over the past two decades, and the goal of these microvascular reconstructions is to restore not only the integrity but also the function of this oropharyngeal anatomy. Common free flaps such as the one pictured here, include radial forearm as well as lateral arm free flaps. These are of particular interest because these are sensate flaps, and you can reinnervate this area and help the patients with regards to swallowing function. If some mandible is lost, you can use fibular free flaps; and also, if you do commando procedures or composite resections in which you have to take skin mandible as well as mucosa, you can use scapular free flaps. The scapular free flaps are important and they provide two skin paddles both for the mucosal lining as well as the outer skin lining.

With regards to prognosis, patients with early stage cancer generally do well and, if they are going to die, they are going to die of unrelated disease or second primary tumors. Patients with advanced disease usually die from local regional occurrences or distant metastasis. I reviewed the literature to find data with regards to prognosis, and one thing I learned is that you could get data basically on any surgery or radiation and find favorable outcomes. I tried finding papers that specifically looked at each subsite, such as pharynx, tonsil, and base of tongue; and I tried to summarize it here for us and with regards to prognosis. The reason this was a challenge is that most papers are not necessarily publishing data with regards to overall survival. They always talk about local regional control. But based on what I sifted through, these are some of the studies I found that I thought were very interesting.

With regards to posterior pharyngeal wall carcinoma, in 1990, Spiro, from Sloan Kettering, looked at 78 patients. All comers treated with surgery with or without radiation therapy postoperatively and at two-year followup, he had a 49% survival rate for these pharyngeal cancers. Schwaab, in 1983, looked at 24 patients treated with chemoradiation at three-year follow-up, and his study for pharyngeal wall sites was 60%. With regards to study that looks particularly at base of tongue, Harrison, in 1992, looked at 36 patients treated with radiation therapy and at two-year follow-up, and he quoted survival rates of up to 87%. Kraus, the counterpart, looked at over 100 patients treated with surgery and at five-year survival, noted about 65% survival. With regards to tonsillar cancer, it is difficult to find statistics on overall survival of just single modality treatments. Most of the treatment was combination treatment with both surgery and radiation therapy. Perez, in 1982, looked at 218 patients and found an overall survival at three years at 45%, and Amornmarn, from The Netherlands, looked at 185 patients and noted a five-year survival rate of 61%. With regards to soft palate carcinoma overall survival, Keus, in 1988, looked at 146 patients treated with radiation therapy, and three-year survival was quoted at 59% and five-year at 52%. Medini did a similar study but with less patients (24), and noted three-year survival of 81%.

Where do I think the future of this disease is going? I think disease control is going to get better and better as we find more cytotoxic agents that have fewer side effects. Research is ongoing. And, again, the intensity modulator radiation therapy is only in its infancy, and is only going to get better, where we can target the tumors and spare some of the other important key structures.

Basic science research cannotbe stressed enough with regards to cancer biology. I think there is still lot to learn with regard to tumor markers, and identifying which tumors would do better with surgery versus radiation. In addition, the basic science with regards to human papillomavirus may yield better results and outcomes for our patients.

Lastly, the one thing I would like to stress is that clinical trials cannot be stressed enough, in that we need better clinical trials involving multiple institutions. When I reviewed the literature, you could find arguments for surgery or radiation therapy, and there is really no gold standard or consensus. I think that if we combine multiple institutions, with strict protocols, I believe the gold standard would be able to be obtained.

In conclusion, I want you to remember that oropharyngeal cancer really needs a multidisciplinary approach. There will always be a role for the surgeon in this type of cancer, but we have to rely on medical oncology, radiation oncology, or speech therapists, as well as our reconstructive surgeons. My experience in reviewing MD Anderson’s 60-year experience is that the data is ongoing, being analyzed, but I found so far that there has been a younger trend in the patient population, and there is less tobacco burden in these patients. Again, ongoing research with regards to human papillomavirus will be quite interesting to see. Lastly, the true standard program for treatment is yet to be defined. But it seems like the combined modalities of chemoradiation are really promising for the future.

Case Presentation:

JM is a 55-year-old female referred by her primary care physician for persistent right neck mass with no other associated symptoms. The patient first noted the neck mass six months prior to presentation. The mass failed to resolve with a course of antibiotics. Two attempts at fine needle aspiration were non-diagnostic. She denied having odynophagia, otalgia, hemoptysis, unexplained weight loss, or difficulty breathing. Other than mild hypertension, she had no other major medical problems. Social history revealed that she has smoked one pack per day over the previous thirty-years. She denied alcohol use or IV drug use.

Physical exam revealed a healthy appearing woman. Palpation of the neck revealed a right level II neck mass that was fixed and non-tender, measuring approximately five centimeters in size. Oral examination revealed right tonsillar asymmetry, but no other masses or lesions. Flexible fiberoptic examination and the remainder of her head and neck exam were unremarkable. A cranial nerve examination was normal.

Preoperative chest x-ray, cell blood count, electrolytes, and liver function tests were normal. A CT scan of the neck showed several enlarged lymph nodes along the right internal jugular vein, with the largest measuring approximately 5 centimeters.

The patient was taken to the operating room for direct laryngoscopy, esophagoscopy and directed biopsies. Frozen section biopsies revealed squamous cell carcinoma originating from the right tonsil. The patient was diagnosed with a T1N2bM0 squamous cell carcinoma of the right tonsil.

She has since undergone evaluation by the radiation oncology and medical oncology services. She is currently undergoing treatment with combined chemoradiation therapy.

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