-------------------------------------------------------------------------------- TITLE: SQUAMOUS CELL CARCINOMA OF THE OROPHARYNX SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: APRIL 20, 1994 RESIDENT PHYSICIAN: Ramtin Kassir, MD FACULTY: Christopher Rassekh, MD DATABASE ADMINISTRATOR: Melinda McCracken, M.S. -------------------------------------------------------------------------------- "This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion." I. ANATOMY A. The pharynx extends from the plane of the hard palate to the lower border of the cricoid cartilage. The oropharynx is that portion of the pharynx that extends form the plane of the hard palate superiorly to the plane of the hyoid bone inferiorly and is continuous with the oral cavity. It includes four different sites: (1) the base of tongue, (2) the soft palate, (3) the tonsillar area (fossa and pillars), and (4) the posterior pharyngeal wall. B. The faucial arch includes both the surfaces of the entire soft palate and uvula, the anterior border and base of the anterior tonsillar pillar, and the line of the circumvallate papillae. C. The base of the tongue extends from the line of the circumvallate papillae to the junction with the base of the epiglottis and includes the pharyngoepiglottic and glossoepiglottic folds. D. The lateral wall of the oropharynx is made up of the tonsil and tonsillar fossae. The posterior tonsillar pillar, the narrow lateral wall, and the posterior wall make up the pharyngeal wall. The tonsillar fossa, which harbors the palatine tonsil, is bounded anteriorly by the anterior tonsillar pillar (palatoglossus muscle) and posteriorly by the posterior tonsillar pillar (palatopharyngeal muscle). The internal carotid artery is just lateral and posterior to the tonsillar fossa. E. The posterior pharyngeal wall of the oropharynx begins at the inferior limit of the nasopharynx around the soft palate and extends inferiorly to the epiglottis. This wall is composed of mucosa, submucosa, pharyngobasilar fascia, underlying superior constrictor muscle, and buccopharyngeal fascia. The buccopharyngeal fascia acts as a natural barrier to prevent posterior extension of carcinoma to the prevertebral fascia. F. The major blood supply to the tonsil is the tonsillar branch of the facial artery. Other involved vessels include the ascending pharyngeal and dorsal lingual arteries and the palatine branches of the internal maxillary and facial arteries. II. PATHOLOGY A. Precancerous lesions may occur in the oropharynx but to a lesser extent than in the oral cavity. These include leukoplakia secondary to hyperkeratosis with or without atypical changes, erythroplasia, lichen planus, and nicotine mucositis. The palate is the site most likely to be involved with any of these changes. B. More than 90% of malignant tumors of the oropharynx are squamous cell carcinoma. These are separated histologically into nonkeratinizing, keratinizing, verrucous, spindle cell, and adenoid squamous carcinoma. 1. Nonkeratinizing carcinomas may be well or poorly differentiated. Classically they spread submucosally and have a "pushing" margin. Keratinizing lesions tend to be ulcerative and fungating, have less of a tendency for submucosal spread, and have infiltrating margins. In general, the degrees of differentiation and keratinization of the primary tumor are less relevant than the primary tumor's location, size, stage, and extent of deep invasion. 2. Verrucous carcinoma occurs rarely in the oropharynx and more often in the oral cavity. It is a histologic variant of a well-differentiated squamous cell carcinoma. 3. Spindle cell carcinomas are variants of squamous cell carcinoma and are not primary connective tissue tumors. Histopathology reveals a spindle-shaped mesenchymal cell resembling anaplastic carcinoma, with various mixtures of squamous cells. 4. Adenoid squamous carcinoma is a rare variant and occasionally occurs in the base of tongue. These lesions must be distinguished from adenoid cystic tumors, which originate in the minor salivary glands in this area. III. INCIDENCE A. In the US, of the almost 1 million new cancers diagnosed each year, approximately 7000-9000 are in the oropharynx. B. The age of patients is decreasing. Tumors are now being seen more in the fourth and fifth decades of life, rather than in the 60 to 70 year age group. C. Male to female ratio is ~ 4:1. IV. ETIOLOGY A. Most significant factor is use of tobacco (although correlation is less than with SCCA of the oral cavity) 1. Certain habits ( reverse smoking, smoking cheap cigarettes with high concentrations of toxins, and chewing tobacco combined with slate, lime, or betel nut leaves) seem to increase tobacco's carcinogenic potential. 2. Relative risk of developing a specific type of cancer depends on the susceptibility of a tissue to various concentrations of tobacco smoke constituents and their metabolites B. Most evidence supports the view that alcohol abuse increases the risk of these cancers: 1. Ethanol appears to act synergistically with tobacco and together these are responsible for over 75% of upper aerodigestive tract cancer deaths 2. Carcinogenesis occurs by cytotoxicity of ethanol and its metabolites and inducing effect on microsomal enzyme activity C. Also appears to be associated with: poor nutrition, syphilis, local mucosal irritation, and poor oral hygiene D. There seems to be a relationship between papillomavirus and cancers of the tonsil. DNA changes associated with papilloma virus have been documented in some patients with tonsillar carcinoma. E. Role of immune deficiency in patients with SCCA of the oropharynx supported by impaired IL-2 secretion F. "Field cancerization" describes multiple primary cancers concurrently in the same patient in the same area. Groups of cells may be stimulated to form cancers by cigarettes, alcohol or other irritants. In the oropharynx, this is most common on the soft palate. V. DIAGNOSIS A. Presentation 1. Early lesions are often asymptomatic creating the biggest problem in treating cancers of the oropharynx, which is their late diagnosis and thus advanced stage. 2. Pain is the most common symptom, usually a unilateral sore throat, pain commonly due to a secondary infection of the tumor, otalgia can be referred pain from the glossopharyngeal nerve to the petrosal ganglion to Jacobson's nerve to the tympanic cavity 3. Neck mass often is the presenting symptom, large base of tongue lesions can produce a "hot potato" voice, other symptoms can be odynophagia, dysphagia, trismus, and fetid odor B. Evaluation 1. Thorough head and neck evaluation and rest of physical examination - bimanual palpation is very important 2. Biopsy can most often be performed in the clinic 3. A transoral fine needle aspiration of the tumor can be performed in the clinic if conventional incisional biopsy is not possible - fairly good results using this technique has been described in the literature 4. Radiography should be used if bony involvement is suspected - plain films and panorex films can have false negative findings in ruling out mandibular invasion - CT scan can be very valuable in determining mandibular invasion and also in assessing a No neck for possible nonpalpable enlarged lymph nodes 5. Operative endoscopy should be performed to rule out synchronous tumors of the upper aerodigestive tract 6. Examination of the tumor under general anesthesia should be performed because these lesions are often painful and the true extent of the lesion on palpation in clinic may not be readily apparent 7. Lesions involving the mucosa of the soft palate, tonsil or floor of mouth often have borders that are indistinct in which case in vivo staining with 0.2% toluidine blue may be used in order to help determine where a biopsy should be taken V. STAGING A. The American Joint Committee (AJC) staging system is that which is now generally used. B. Oropharynx tumor AJC classification Tis Carcinoma in situ T1 Tumor 2 cm or less in greatest dimension T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension T3 Tumor more than 4 cm in greatest dimension T4 Tumor invades adjacent structures (e.g., through cortical bone, soft tissues of neck, deep (extrinsic) muscle of tongue) C. Regional lymph node, distant metastasis and stage grouping has been covered in the past VI. GENERAL MANAGEMENT CONSIDERATIONS A. Oropharyngeal tumor treatment options have changed over time. Initially these tumors were approached with surgery to the primary and metastatic site. Later the emphasis on therapy shifted to radiation as the primary treatment modality, and over the past several years a shift toward more combined therapy with radiation and surgery has occurred. Four current approaches to treatment are: 1. Radiation alone with external beam therapy 2. Radiation for cure with surgical salvage as required 3. Surgery alone 4. Planned combined therapy with surgery, radiation, and/or chemotherapy B. Radiation alone 1. It is generally accepted that early lesions (T1,T2) may be treated equally effectively by radiation or surgery; however, as the staging increases, the effectiveness of a single-modality therapy declines dramatically. Also, the true value of radiation alone is difficult to extract from the literature. Mixed in with what is called "radiation treatment" are radiation to the primary tumor combined with neck dissection and operation after radiation failures. In the US, early tumors are likely to be irradiated and advanced tumors usually treated by surgery alone or combined therapy. 2. Tumor recurrence in irradiated patients is usually local which is currently thought to be due to tumor hypoxia which results in radioresistance of the tumor. However, it is also possible that the tumors are simply under dosed. The tumor dose required in a large T3/T4 lesion may exceed the external beam radiation tolerances of the normal surrounding tissues. Recent reports have suggested that a dose of at least 8,000 - 10,000 rad is required for local control of a tumor greater than 3-5 cm in diameter. 3. Radioactive interstitial implants have a role in both primary treatment of tumors and treatment of recurrent cancers of the oropharynx. C. Radiation with surgery for salvage 1. The concept of radical radiation for cure with surgery for salvage does not appear as attractive for oropharyngeal cancer as it does for laryngeal cancer. This is primarily due to the increased complication rate of an operation performed in a heavily irradiated field and some evidence that preoperative radiation may not decrease local recurrence rates but actually increase them. D. Planned combined radiation and surgery 1. There are some authors who believe that most oropharyngeal cancers, including advanced lesions, can be treated adequately by radical ablative surgery without the use of adjuvant radiotherapy; however, at most institutions a combination of surgery and post-operative radiation is advocated. This theoretically offers an improved chance for success and has been proven to decrease local recurrence rates yet evidence that 5 year survival rates are significantly improved is lacking. Radiation doses ranging from 6,000 to 7,200 rad post-op are now being recommended and they should begin within 5-6 weeks post-op if they are to be of maximum benefit. E. Chemotherapy 1. The role of adjuvant chemotherapy in a multimodality treatment regimen remains continues to evolve. Intra-arterial infusion of chemotherapy has been described in the literature as being less likely to produce serious systemic toxicity and requiring a shorter period than systemic neoadjuvant chemotherapy. Chemotherapy aimed at increasing local regional control rates in advanced lesions has been used with good response in some patients without additional morbidity after surgical resection or postoperative radiation therapy. There seems to be no difference between the induction and sequential groups. If the pathology specimen reveals microvascular invasion, adjuvant chemotherapy is recommended since the prognosis is worsened. However, a high rate of local toxicity accompanies this method and it frequently shortens the desired course of therapy. There has also been some evidence of significantly increased rates of distant metastasis noted in patients treated with preoperative chemotherapy possibly secondary to decreased immune responses to the tumor during therapy. F. Consideration of the Neck 1. The metastatic potential is related to the size of the tumor, the depth of tumor invasion, and the quantity of lymphatic channels that supply the primary tumor site. At least 50% of all patients with oropharyngeal tumors have clinically positive necks; the percentage of occult-positive necks is significant and bilateral spread is not uncommon (i.e. base of tongue). 2. Some authors have related an increased metastatic nodal spread with less differentiated tumors and ulcerated tumors (versus exophytic tumors with pushing borders). The patient's immunologic system may be affected by various nutritional and other unknown factors. A previous h/o infection or radiation to the cervical area also may affect the metastatic rate. 3. The incidence of No necks in pts with oropharyngeal tumors varies according to the site of lesion. The soft palate, anterior tonsillar pillar, and retromolar trigone have a higher incidence of No necks, probably because these are sensitive as well as easily visible areas and lesions are diagnosed at an early stage. Base of tongue and tonsillar fossa lesions, however, have a low incidence of No necks. These areas are less painful and even T1 lesions typically appear with a clinically positive neck. If pts with No necks who have primary lesions in the oropharynx are not treated with some therapy to the neck area, 10-25% will develop positive neck nodes later. The prognosis for patients who have had neck disease treated later is worse (increased risk of distant mets) than if they had been treated initially. Treatment of the primary oropharyngeal lesion and observation of the clinically negative neck for future disease generally are not recommended. Since the metastatic rate in oropharyngeal lesions is reasonably high and lymphatic supply to all these areas is abundant, the initial treatment plan should involve therapy to the primary site as well as to associated local and cervical lymphatics. 4. Tumors of the oropharynx generally metastasize in an orderly fashion from the high cervical first- echelon lymph nodes inferiorly to involve the midcervical and lower cervical areas. However, the aggressiveness of the tumor, concurrent local or cervical inflammation, the history of previous treatments to the neck, and fibrosis of the lymph channels may all combine to vary the filtering and trapping functions of the nodes and may result in unpredictable metastatic spread. 5. Except for those very small and superficial tumors, it is generally accepted that some form of treatment should be addressed to each neck. Necks that are negative on exam can be treated with by either functional neck dissection or external XRT. (The supraomohyoid dissection not recommended because of the risk of occult-positive nodes remaining in the inferior portion of the neck). In the treatment of clinically negative necks in advanced cancer there are no significant differences in the rates of neck cancer recurrence among the elective neck irradiation, dissection, and combined treatment groups. When there is a choice, the neck dissection should be incontinuity with the primary lesion. Higher recurrence rates are reported with discontinuous dissections. Clinically positive necks must be treated with surgery, XRT, or combination. For N1 or N2a disease, RND is considered adequate treatment. XRT is performed initially if it is the principal modality for the primary lesion of if a cervical metastasis is fixed or questionably resectable. Combined therapy of XRT after the neck dissection is indicated for "high-risk" cases, such as those with large or multiple positive nodes at several levels, extracapsular spread, and preoperative node fixation. The worst results (14% survival) are generally in patients who are irradiated for surgical failure of the neck disease. Results for surgical salvage following XRT failure are better (42%). Recurrence rates are lower in the combined therapy group than in the surgical group of patients with N2 and N3 stages of disease. G. Surgical Therapy A. Limited intraoral excision of oropharyngeal tumors generally is condemned except in unusual circumstances. Most often the operation involves resection of the primary site and some type of neck dissection. The approach to resection of larger primary tumors of the oropharynx involves consideration of the mandible. Traditionally, removing a portion of the mandible with the primary lesion was considered necessary; however, surgeons are now trying to preserve the mandible when it is considered safe in terms of tumor resection. It has been demonstrated that malignant cells are not found in the periosteal lymphatics unless the gross tumor lesions are in direct contact with the mandibular mucoperiosteum. For lesions lying close to but not directly involving the lingual surface of the mandible, partial marginal mandibular resections may be performed as these resections ensure adequate margins yet preserve the continuity of the mandible. Nuclear scanning, plain radiographs, CT (denta) scans are available to determine bone involvement but the most accurate method seems to be direct intraoperative inspection. If the periosteum strips cleanly from the bone, then invasion of the bone is unlikely. B. Approaches 1. Lip split or visor flaps 2. Anterior mandibulotomy 3. Median translingual pharyngotomy 4. Transhyoid pharyngotomy 5. Lateral pharyngotomy 6. Associated procedures a. Supraglottic laryngectomy b. Total laryngectomy F. Reconstruction 1. Primary closure - guard against too tight of a closure because of the possibility of tethering of the tongue, difficulty with swallowing or fistula formation 2. Skin grafts - free or dermal are commonly used to close lateral posterior tongue and tonsil areas, immobilization improves take 3. Local flaps - tongue flap a. Advantages - ease of accessibility, lack of cosmetic defect and excellent blood supply b. Disadvantages - possible poor speech and deglutition 4. Regional flaps - cutaneous and myocutaneous a. Cutaneous (1) forehead flap (2) deltopectoral flap (3) nape-of-the-neck flap b. Myocutaneous (1) pectoralis major (2) trapezius (3) sternocleidomastoid 5. Free flaps a. Advantages - large amount of tissue is available and good blood supply b. Disadvantages - time-consuming, requires personnel well trained in microvascular techniques and recipient defect must have an appropriate artery and vein available for reanastomosis I. Complications 1. Radiation (dose related) a. mucositis b. decreased taste sensation c. dysphagia and weight loss d. scarring and fibrosis e. ulcerations of the radiation area f. tracheitis g. osteoradionecrosis h. alterations in blood supply 2. Surgery a. fistula formation b. long-term oropharyngeal dysfunction c. aspiration d. poor speech e. complications associated with neck dissection and tracheostomy VII. TREATMENT OPTIONS FOR SPECIFIC SITES A. Tonsil and Anterior Tonsillar Pillar 1. Most common location for tumors within the oropharynx 2. May spread into retromolar trigone, mandible, pterygoid muscles and parapharyngeal space 3. Fossa lesions have a higher risk of lymph node metastasis compared with lesions limited to the anterior pillar, contralateral neck metastasis is reported and increases as more structures are involved (especially midline soft palate) 4. Some 25% present with a neck mass as their only symptom 5. XRT is recommended for early T1N0 and T2NO lesions. Primary treatment by surgery usually is not recommended initially because of functional problems inherent in resections to this area compared to the high success rate and low morbidity with XRT. Limited surgical resection of small lesions w/o concomitant treatment to the local and regional lymphatics is inappropriate. XRT fails to cure approximately 20% of T2 and 30-50% of T3 lesions. In these lesions surgery is recommended if the primary lesion fails to show adequate regression at 5000 rad. 6. T1/T2 with neck disease can be treated with primary XRT or surgery - an advantage of surgery is that it allows examination of the neck specimen to determine if combined therapy (post-operative XRT) would be of benefit since demonstration of neck metastasis upon initial therapy literally reduces the cure rates in half 7. Advanced cancers of the tonsil (stage III/IV) generally are treated with combined therapy (A composite resection followed by postop XRT). Planned preop XRT is recommended only if large fixed nodes are found at the initial examination. 8. Unresectable tumors are usually treated with chemotherapy, combination CTX/XRT or laser treatment. B. Base of tongue 1. About 1/4 as common as cancers of the anterior 2/3 of the tongue 2. These lesions are usually diagnosed at a later stage and are notorious for early deep invasion of the muscles of the base of tongue 3. Lymph node metastasis is quite common: a. 60-75% with positive node on initial visit b. 20-30% with bilateral nodes c. perhaps 50% with occult nodes 4. T1 lesions are rare 5. T1/T2 typically resected by way of a mandibular osteotomy and neck dissection (possibly bilateral) with analysis of neck contents as to possible post-operative XRT 6. Advanced cancers treated with combined therapy 7. The overall cure rate for most series, regardless of therapeutic modality is usually about 30%. C. Soft palate 1. Tumors of the soft palate, especially midline, have a bilateral metastatic rate that is significant and the contralateral metastatic rate is higher with a negative ipsilateral neck in contrast to tonsillar and pillar lesions 2. Small, well-circumscribed lesions that are superficial and sometimes multicentric ("devastated epithelium") can be treated either surgically or with XRT: a. Surgery - usually recommended for tiny carcinomas of the uvula. Larger resections of the palate for more advanced lesions w/o XRT increase the chances for local and regional metastases.Options includes transoral cold-knife excision, hot-knife excision, laser vaporization, laser excision and cryosurgery b. radiation - treats not only the primary lesion but the local area as well, including any epithelium that may have malignant changes not obvious to the physician. XRT also treats the local lymphatics, which is important if the incidence of bilateral neck disease is to decrease. c. N0 neck is not treated 3. Large soft palate cancers have more tumor mass with both sides of the neck being at risk a. surgical resection is often mutilating in that function is seriously altered b. XRT control rates are fairly good and function post-treatment certainly is better thus external beam treatment of tumor and both necks is usually recommended (can implant smaller tumors) - if needed about one of four patients can be salvaged surgically after radiation failure c. advanced lesions treated in combined manner however survival rates are poor, especially with advanced neck disease. Cure rates with XRT alone for T1NO are 80-90% and for T2N0 70-80%; for T3 and T4 lesions the cure rates drop dramatically to 20-30%. ---------------------------------------------------------------------------- BIBLIOGRAPHY 1. Bailey BJ, et al. Oropharyngeal Cancer, in Head and Neck Surgery-Otolaryngology, pp1274-1285. 2. Cummings CW, et al. Otolaryngology- Head and Neck Surgery. Malignant Neoplasms of the Oropharynx, pp 1306-1353. 3. Close LG. Microvascular invasion and survival in cancer of the oral cavity and oropharynx. Arch Otolaryngol Head Neck Surg 1989;115(11):1304-9. 4. Close LG. 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