Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Squamous Cell Carcinoma of the Tonsil Carcinoma of the tonsils is the most common type of oropharyngeal malignancy with squamous cell carcinoma making up the majority of tonsillar cancers. Approximately 12,000 new cases are diagnosed each year. Tonsillar cancer accounts for 1.5% to 3.3% of all cancers and is second in frequency to laryngeal cancer among upper respiratory tract malignancies. Historically it is diagnosed after the fifth decade of life in drinkers and smokers, but cases are appearing in the 30-year-old group with no history of alcohol or tobacco. We will look at recent investigations suggesting a viral etiology in this younger age group. Tonsillar cancer is more common in men with a male to female ratio of four to one. As many as 90% of patients can present with regional metastasis, and 25% to 45% of N0 necks may harbor an occult metastasis. Five to 10% will have a synchronous second primary, and most cases present with late stage disease, which has led to the perception that tonsillar carcinoma has a poor prognosis. We will see, however, that early diagnosis can have up to a 90% five-year survival. We will start with some anatomy. The nasopharynx extends from the choana to the superior surface of the soft palate. The oral cavity extends from the cutaneous vermilion junction of the lips, and it extends back to the junction of the hard and soft palate and the circumvallate papillae. Then the oropharynx starts at that same junction, the hard and soft palate, the tonsillar pillars and the circumvallate papillae and extends to the superior surface of the hyoid bone. This includes the base of tongue and the posterior oropharyngeal wall. It also includes the tonsillar pillars as well as the palatine tonsils. Following that is the hypopharynx, which starts at the hyoid bone and goes down to just below the level of the cricoid. It includes the piriform sinus and the postcricoid area. First described by the German anatomist, Heinrich Wilhelm Godfried Von Waldeyer, Waldeyer’s ring is a ring of lymphoid tissue formed by the lingual tonsils over the base of the tongue, the palatine tonsils, which is what we are discussing today, and the nasopharyngeal tonsils (the adenoids). The ring of lymphoid tissue appears during the first few months of life and is prominent during childhood and then slowly regresses from puberty on. Embryologically, the tonsillar fossa and palatine tonsils are derived from the endoderm of the first and second pouch. As these pouches develop their connection with the pharyngeal lumen, the pharyngobranchial duct is obliterated. If it is not obliterated then that is how you get a branchial cyst or sinus that develops. The second pharyngobranchial duct is between the second and third arches and it is believed to open in the tonsillar fossa. The palatine tonsils fit in the tonsillar fossa between the anterior and posterior tonsillar pillars, and these are derived from the second and third branchial arches. This is an H&E stain of a typical tonsil. The association of lymphatic tissue and an overlying stratified squamous epithelium or capsule are the identifying histologic features of this organ. The mucus type glands below are small salivary glands that open up on the surface of the tonsils. Again, this stratified squamous epithelium forms the tonsillar capsule and it dips down into these invaginations called crypts. The capsule also covers the deep surface of the tonsil, which is separated from the superior constrictor muscles by thin areolar tissue. The lymphoid tissue is arranged as nodules with germinal centers surrounded by lymphocytes, and this is just a blood vessel. Seventy-five percent of tonsillar neoplasms are malignant, with squamous cell carcinoma making up the vast majority of these. Lymphoma is the next most common malignancy of the tonsils, followed by salivary gland tumors and a very small number of metastases from other sites. The TNM staging system is designed to describe the anatomic extent of cancer before treatment. Its purpose is to aid in treatment planning, to facilitate communication between different treatment centers, and to estimate prognosis. T stage for a primary oropharyngeal tumor is as follows and you can see that it is based on size until you get to T4, at which point it is based on invasion of adjacent structures. Our patient had a 3.0cm lesion, which you can see falls within T2. Lymph node and metastatic staging is the same as for other head and neck cancers. Our patient had no palpable lymph nodes and no distant metastasis. Overall staging is as follows: Stage 1 is a tumor less than 2.0cm with no nodes or metastasis. Stage 2 is a tumor that is between 2.0cm and 4.0cm with no nodes or metastasis, and this is what our patient was staged as. Stage 3 is either a tumor greater than 4.0cm with no nodes or metastasis, or any size tumor with a single ipsilateral lymph node less than 3.0cm. Stage 4 includes any tumor that invades adjacent structures, any lymph node disease that is greater than 3.0cm, multiple or bilateral, and any distant metastasis. There have been many studies to identify other prognostic factors, but primary tumor and neck node status are the only consistently agreed upon factors that significantly influence local regional control and disease-free survival in tonsillar squamous cell carcinoma. The TNM staging gets the most predictive prognosis, again based on the primary tumor and nodal status. You can see that the local, regional, and five-year survival decrease, and the prognosis decreases as you increase in stage. So the TNM gives the most predictive prognosis based on primary tumor, but there are other examples in the literature to try to identify other prognostic factors. This first study out of Oslo evaluated 310 patients with tonsillar squamous cell carcinoma, and they found that age greater than 60 as well as male gender were associated with a shorter disease-specific survival. Another study out of Alberta, however, looked at 102 patients and found that when factors were stratified by stage there was no significant association between age, gender, and survival. They did find that an ulcerated lesion was a significant predictor of poor outcome as compared to a non-ulcerated lesion and there are multiple similar studies, each demonstrating or discrediting various prognostic factors, histologic grade being another one. But again, the most predictive prognosis comes from tumor stage and nodal status. Patients with tonsillar cancer can present with a number of symptoms. Many patients will be seen with an asymmetric enlarged tonsil as seen here. However, only 5% of enlarged tonsils turn out to be malignant. Patients will commonly present with odynophagia, an isolated neck mass, dysphagia, trismus, a muffled voice, and otalgia. Twenty percent of people ultimately diagnosed with tonsillar cancer initially present with an isolated neck mass. Another impressive statistic is that 64% to 90% of patients already have neck disease when they present and, as mentioned earlier, most tonsillar cancers present in later stages. Evaluation always begins with a thorough history and physical, making sure to elucidate any tobacco or alcohol use. If there is an obvious tonsillar lesion, palpation of the base of tongue and oral cavity is essential in determining the extent of the primary mass. Flexible nasopharyngoscopy allows visualization of possible spread to the hypopharynx. A complete head and neck exam must be done to evaluate for both regional mets and a second primary. As previously mentioned, 64% to 90% of patients will have palpable neck disease when they present. In addition, there is a 5% to 10% incidence of synchronous second primary in head and neck squamous cell carcinoma. Fifty percent of these will occur in the head and neck. The lung is the next most common site. Evaluation of dentition is important so that appropriate referral for dental extraction can be made if radiation is going to be part of the treatment. Biopsy of the primary lesion can confirm the diagnosis, and a CT of the neck will provide more information about the extent of the disease as well as any non-palpable lymph nodes. Chest x-ray and labs, direct metastatic workup: Again there is a 3% to 5% incidence of distant metastasis on presentation and mandatory panendoscopy is controversial for primary lesions that are identified in the office. If a panendoscopy is not done, the esophagus must be evaluated with an upper GI study. Most of head and neck primaries can be identified on physical exam and this includes flexible nasopharyngoscopy, but 10% of the time cancer of the head and neck will present initially as a cervical nodal metastasis without an identifiable source. In 2% to 8% of these cases, a primary tumor is never found. Patients benefit from identification of the primary tumor because it reduces radiation fields and directs surveillance for recurrent disease. Evaluation and treatment of an unknown primary is another topic in itself, but it is relevant today because often the tonsil harbors the occult malignancy. In 1944, Dr. Hayes Martin described the diagnostic approach to the unknown primary tumor in the head and neck and we still use this today. He advocated an exam under anesthesia that included direct laryngoscopy, bronchoscopy, and rigid esophagoscopy or panendoscopy with directed biopsies of sites that are most likely to harbor the occult tumor. These sites are the nasopharynx, base of tongue, and piriform sinus. Biopsy of the tonsillar fossa has not always been included in the routine evaluation of an unknown primary, and biopsy alone may not even be adequate. Small tumors can hide in the crypts of the tonsils and may not be visible from the surface. Superficial biopsies at the time of panendoscopy may miss the tumor. This is a slide from a tonsillectomy specimen in a patient with invasive carcinoma that was missed on biopsy. This is a full-thickness section with the surface epithelium depicted here and a deep tonsillar crypt depicted here, and this is where, upon tonsillectomy, they identified invasive squamous cell carcinoma. So again, on the superficial biopsy, the epithelium looked fine for these three and once they took out the tonsil and evaluated the deeper tissue, they found the invasive squamous cell carcinoma. This has led some authors to recommend routine ipsilateral tonsillectomy in the workup of an unknown primary. They argue that the tonsils, unlike the nasopharynx or base of tongue, is amenable to complete resections with minimal morbidity. One study reports that 18% of a study population with an unknown primary were found to have a tonsillar primary by doing an ipsilateral tonsillectomy. Other surgeons advocate a bilateral tonsillectomy, both to catch the rare case of bilateral disease and to bestow anatomic symmetry. Leaving one tonsil behind can confound future exams, as this can appear suspicious for a pathologic asymmetry rather than an iatrogenic one. In a study out of Johns Hopkins, by doing bilateral tonsillectomies, 39% of patients with an unknown primary were found to have tonsillar squamous cell carcinoma. One patient had squamous cell carcinoma identified in both tonsils. Two caveats in evaluating apparent lymph node metastasis: Frist, make sure you’re actually working up a cervical node and not a supraclavicular or low posterior triangle node. Cervical nodes are associated with upper airway digestive primaries while a supraclavicular or low posterior triangle metastasis is associated with primaries below the clavicle, like breast, lung, or stomach, and this will require a different workup entirely. Second, sometimes the cervical mass is cystic and can be confused with a branchial cleft cyst. In this situation FNAs are notoriously unreliable, with a false negative rate of 67%. In addition, radiology is nonspecific. It is difficult to tell, for example, if this is a branchial cleft cyst or a metastatic lymph node that has undergone cystic degeneration. An excisional biopsy would give you the diagnosis, but if it is cancer, ideally the initial definitive procedure in the neck is a formal neck dissection. Some authors recommend excising the mass, sending it for intraoperative frozen section, and then extending the incision for a formal neck dissection if the frozen section is positive for malignancy. Decision-making should be directed by clinical suspicion, which relies heavily on the age of the patient. Children and adolescents rarely have head and neck squamous cell carcinoma, whereas adults with a history of tobacco and alcohol use are at increased risk for malignancy. In discussing the treatment of tonsillar carcinoma, it is easiest to break it down into two segments. First, the treatment of the primary tumor and second the treatment of the neck, both the clinically negative and positive neck. The modalities for treating most head and neck cancers are radiation, surgery, or a combination of the two, and the same is true for the treatment of tonsillar carcinoma. Prior to 1990, most tonsillar cancer was treated with surgery. Depending on the stage at presentation, surgery ranged from a transoral wide local excision to a composite or commando resection of the tongue, jaw, and neck. Morbidities ranged from simple postop pain to chronic dysphagia, aspiration, speech problems, and disfiguring defects requiring reconstruction. Advances in radiotherapy have resulted in a trend over the last 10 to 15 years towards primary radiation for early tonsillar cancer. Reports suggest that radiotherapy for earlier lesions is associated with less morbidity and has the same survival rates as surgery. In general, these are the arguments for and against each modality. Surgery, it has been argued by some, achieves better local and regional control. Free tissue reconstruction allows for exc ellent functional restoration, and you can reserve radiotherapy for recurrences or second primaries. Surgery also allows pathologic staging of the neck and aids in directing adjuvant therapy, and you can avoid the complications of radiation, which include xerostomia and osteoradionecrosis. It has been argued that radiation has similar survival rates for early lesions. It results in less functional morbidity from a speech and swallow standpoint, and salvage surgery is still an option. There are fewer severe or fatal complications with radiation, including osteomyelitis and carotid blowouts. So what does the literature show? There are many studies that present data from either the surgical treatment group or radiation treatment group alone, but few actually compare the two modalities in a population from the same institution, and nearly all studies on treatment outcomes are retrospective. One study comparing surgery versus radiation, a single modality treatment of tonsillar carcinoma, comes from the Roswell Park Cancer Institute. They retrospectively analyzed 76 patients, 56 of whom had surgery and 20 of whom had radiation. All patients in the radiation arm were surgical candidates who declined primary surgical therapy. Sixty-three percent of the surgery arm and 80% of the radiation arm presented with Stage III or IV disease, and this was a significant difference. The local control rates for each stage were not significantly different between the surgery and radiation arms, although the trend was towards improved local control with surgery in the later stage. Although this is not significant, it is just a trend. Disease-free survival and disease-specific survival, however, were both significantly improved in the surgical arm for stage III and IV disease, and this was significant. Again, in the early stages, surgery and radiation therapy are equal. Interestingly, the patterns of recurrence, although not significant, were different. There were no contralateral recurrences in the radiation arm, where almost half of the regional failures in the surgery arm occurred in the contralateral neck. The conclusions from this study are that single modality therapy for early lesions, stage I or II is equally effective with either surgery or radiation. In stage III or IV disease, surgery as a single modality offers improved survival than radiation as a single modality; but most authors, including the ones who did this study, agree that combined therapies for late stage disease is more effective than single modality therapy. The UCLA experience compares primary radiation to combined surgery and radiation. Ninety-seven patients diagnosed with tonsillar carcinoma between 1970 and 1990 were studied with respect to local control according to the type of treatment given. Forty patients had a T1 or T2 lesion, and of these, 25 were given primary radiation and 16 were given combined therapies. Fifty-seven patients had a T3 or T4 lesion, 39 patients getting radiation and 18 getting combined. Again, local control between single or combined therapy, 70% and 75% respectively, in the earlier staged tumor was not significant. The difference in the later staged lesions, T3 and T4, was significant. However, single modality therapy with radiation had a local control of 37% and combined therapy had a local control of 63%, and that was a significant difference. With regard to survival, studies have shown that in T1 or T2 disease, the survival is not affected by single versus combined therapy. They are equivalent. For T3 or T4 disease, there are trends that favor combined therapy over single modality therapy for improved survival, but these trends rarely reach significance. Some authors have suggested that there is such a poor prognosis with late-stage disease, and these patients usually have such poor overall health, that it is going to be difficult to demonstrate an overall survival benefit with any therapy. The largest study on survival that reached significance came out of the Netherlands. Over 300 patients with tonsillar carcinoma were evaluated with respect to treatment modality and outcome. A disease-specific survival of 39% in patients treated with radiation alone was significantly less than a 53% disease-specific survival in patients treated with combination therapy. This difference remains statistically significant after adjusting for stage. So there is little argument that for Stage I or II disease: radiation and surgery achieve equivalent outcomes with respect to local regional control and survival. There is data to support improved local regional control of Stage III and IV disease with combined therapy; and while there is not a lot of data that has demonstrated statistically significant survival benefits with combined therapy, most authors agree that Stage III and IV disease is best treated with combination therapy. Oropharyngeal cancers have a known high rate of cervical metastasis. More specifically, up to 90% of tonsillar cancers present as clinically positive nodes and 25% to 45% of N0 necks will have occult disease. In general, if the rate of cervical metastasis is greater than 20% elective treatment of the N0 neck is recommended. For N0 or N1 disease at presentation, either neck dissection or radiation is appropriate therapy and is often directed by the treatment of the primary lesion. N2 or N3 disease has better local control rate if combined therapy is used. Treatment of bilateral neck is recommended when the tonsillar primary extends from the soft palate close to the midline, when there are clinically positive nodes in the contralateral neck, and when the tongue has been invaded. In the N2 to N3 neck, treatment is a radical or modified radical neck dissection plus radiation. In the N0 or even N1 neck, however, what nodal level seems to be addressed? Candela did a retrospective study of 333 patients with squamous cell carcinoma of the hypopharynx or oropharynx to determine the prevalence of neck node metastasis by neck level. Their study was extraordinary in that every single patient had a radical neck dissection, thus detailed pathologic analysis of all cervical lymph node levels was available in all patients. There were 207 cases of oropharyngeal squamous cell carcinoma: 47 presented with N0 necks and 160 had N-positive necks. All patients underwent ipsilateral radical neck dissections, and nine patients underwent a bilateral radical neck dissection. Upon pathologic evaluation of the lymph nodes from each level, this is what was found: In the clinically N0 neck, 0% of level I nodes were positive, 19% of level II nodes were positive, 14% of level III, 9.5% of level IV, and 4.8% of level V. In the N-positive neck, 10% of Level I nodes were positive, 72% in II, 41% in III, etc. Based on the series, the authors demonstrate that Levels II, III and IV are at greatest risk for nodal metastasis from primary squamous cell carcinoma of the oropharynx. Level I was not involved in clinically negative patients but was significantly more so in the N-positive group. Level V is rarely involved in the N0 group, more so in the N-positive group. However, in both these situations, the Level V involvement is always associated with nodal mets and the same is true for the Level I involvement here. The author suggests that in an N0 neck, levels II through IV should be removed and if any nodes were suspicious intraoperatively, Levels I and V should be included in the dissection. If the surgeon wants confirmation of Level II through IV disease before proceeding with Levels I or V, he or she can send frozen sections intraoperatively. Based on this study, the authors suggest that no positive nodes will be missed following this protocol. If pathologic staging is N0 or N1, no further treatment is necessary; and if it is N2 or N3, the patient needs postop XRT. What this study did not include was evaluation of the retropharyngeal lymph nodes. They are known to drain the tonsils. They can be evaluated intraoperatively or treated prophylactically with radiation. This must be done with caution, however, as the vertebra and spinal cord are at risk for radiation injury. In summary, tonsillar squamous cell carcinoma is the second most common upper airway digestive malignancy. If found and treated early, local control and survival is as high as 90% with either surgery or radiation. Retrospective studies suggest that combined therapies for Stage III and IV disease has a survival advantage over single modality therapy. Oropharyngeal malignancies have a high rate of regional metastasis, and the neck must be addressed. Before concluding, I want to mention some current research. There are some promising early survival data with protocols of preoperative chemotherapy and radiation followed by surgery. These data warrant further investigation on the role of chemotherapeutic drugs as radiosensitizing agents. In addition, the role of human papilloma virus (HPV) in tonsillar malignancy is gaining support. I alluded to this earlier. The HPV genome has been isolated within cancer cells but not within normal mucosa, and there is a significant correlation of HPV-negative status in the history of alcohol consumption, suggesting that HPV-negative and HPV-positive tumors may represent different entities with different risk factors. A survival advantage has been demonstrated in HPV-positive tumors further supporting the theory that HPV-positive cancer comprises a distinct clinical and pathological disease entity. Some areas that need to be further investigated include functional outcomes in patients treated for tonsillar cancers. There are some studies out of Memorial Sloan-Kettering that look at patient’s perceptions of outcomes. Patients analyzed their ability to eat in public, their understandability of speech, normalcy of diet, and earning potential. The results from different treatment groups, surgery versus radiation versus combined, were compared and the trend was that function was better after radiation then after combined therapy. Functional status deteriorated when comparing patients with T1 or 2 disease to those who had T3 or 4 disease. And finally, most of the literature is based on retrospective chart reviews, and there is a significant need for prospectively designed studies. Case Presentation RB is an 81 year-old man referred by his primary care physician for “atypical tonsils”. He denies weight loss, odynophagia, otalgia, trismus or change in voice. He does complain of a several month history of dysphagia. Past medical history is significant for hypertension, diabetes mellitus, dyslipidemia, coronary artery disease, and peripheral vascular disease. His past surgical history is significant for AAA repair and bilateral carotid endarterectomy. The patient has no known drug allergies and he takes several anti-hypertensives and oral hypoglycemics. He is also on a statin for high cholesterol. The patient has a 50 pack-year smoking history, but quit 17 years ago. He denies heavy alcohol use. On examination, the patient has an exophytic mass on his left palatine tonsil that is approximately 3 cm in size. The left base of the tongue is firm and the floor of the mouth is soft. There is no neck lymphadenopathy and the rest of the examination, including flexible nasopharyngoscopy, is negative. The patient has poor dentition. The rest of the patient’s work-up, including chest x-ray and liver function tests, is normal. CT scan reveals a left palatine tonsil lesion measuring approximately 2.5 cm. It extends to the posterior wall of the orophyarynx but does not invade the pterygoids, mandible, hard palate, or deep muscles of the tongue. There is no lymphadenopathy. 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