------------------------------------------------------------------------------- TITLE: FLOOR OF MOUTH CANCER SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds DATE: September 1, 1993 RESIDENT PHYSICIAN: Michael D. Bryan, M.D. FACULTY: Christopher Rassekh, M.D. 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. EPIDEMIOLOGY Oral Cavity Cancer 4% of all cancers in men 2 % of all cancers in women 20,000 new cases annually in U.S. 5,000 deaths annually in U.S. Distribution Lip (Descending Tongue frequency) Floor of mouth Gums/Gingiva Buccal Mucosa Palate Retromolar Trigone Floor of Mouth Cancer Male:Female = 3 - 4:1 most often 5th to 6th decades of life 0.5 to 1.0% of all cancers 500 deaths per year II ETIOLOGY Tobacco - 90% of patients use tobacco; 60 - 70% heavy smokers. Smokeless tobacco is now considered to be a higher risk substance than smoking, but this is primarily related to gingival/buccal region lesions Alcohol - 70-80% of patients consume alcohol regularly; 50% are heavy drinkers Nutritional deficiencies - riboflavin, iron deficiency, vitamin A, Immune system depression Chronic irritation Poor oral hygiene III ANATOMY The floor of mouth is the "crescent shaped mucosal covered area that lies above the mylohyoid muscle, is bordered by the lingual surface of the mandible anteriorly and laterally, and the root of the tongue and anterior tonsillar pillars posteriorly." It contains the sublingual glands, portions of the three extrinsic muscles of the tongue (styloglossus, hyoglossus, genioglossus), the submandibular ducts, the lingual nerve and hypoglossal nerve, Blood supply - lingual artery Lymphatics - two discrete plexuses; a superficial and a deep collecting system. The superficial system freely communicates across the midline and drains to level I preglandular nodes. The deep system only communicates across the midline at its most anterior area. The deep system drains the anterior floor of mouth to the same preglandular nodes as the superficial system, but the posterior deep floor of mouth drains to the level II jugulodigastric and jugulocarotid nodes. IV PATHOLOGY More than 90% of floor of mouth (FOM) malignancies are squamous cell carcinoma (SCCA). The remaining approximately 10% are made of minor salivary gland tumors, lymphomas, melanomas, and sarcomas, with all but the minor salivary gland malignancies being rare. (The remaining discussion will center on SCCA because of its prevalence) V CLINICAL INFORMATION Premalignant lesions - leukoplakia and erythroplakia are well known premalignant mucosal conditions. Malignant transformation can be seen with either and its estimated that 2-3% of leukoplakic lesions will display carcinoma in situ on biopsy. Erythroplakia is considered a higher grade premalignant condition and a much higher incidence of CIS, and sometimes microinvasive carcinoma. All such lesions should be biopsied. Synchronous and metachronous lesions - FOM SCCA patients have a 20 - 30% incidence of 2nd primaries; 50% of these will occur n the head & neck .In addition to second primaries, multifocal cancers are more common in the FOM than any other oral cavity area. This along with the high incidence of second primaries supports the theory of "field cancerization" Morphology - lesions are generally either superficial and exophytic, or ulcerative and more endophytic with a grayish shaggy base and heaped up rolled margins; most authors have found clinically that the endophytic/ulcerative lesions are the more dangerous actors. This may be related more to the thickness of the invasive portion of the lesion. Metastasis - palpable cervical metastasis are common, with 30 to 50% of patients presenting with clinically positive neck adenopathy at the initial examination. Unfortunately, non-palpable occult metastatic rate is also quite high: T2N0 - 40% occult metastatic rate T3N0 - 70% occult metastatic rate. Metastatic spread follows the lymphatic drainage and is typically to the submandibular nodes first, followed by upper deep jugular nodes. The most common location of lesions is in the anterior FOM, thus the high incidence of drainage to submandibular nodes. As noted above, the posterior FOM drains directly to the jugulodigastric & jugulocarotid nodes. Rarely, submental nodes are involved. Involvement of more than one level is common in N+ necks. Palpable adenopathy is not always metastatic disease, as 10 - 20% of these nodes are due to inflammation rather than neoplasm. Chief complaint - typically a painful lesion in the FOM, which unfortunately is a relatively late sign. Decreased tongue mobility may be a presenting complaint and indicates likely invasion of the root of tongue, another sign seen in progressed disease. Late presentation may be secondary to lack of obtrusive symptoms until branches of lingual nerve or the muscles of the tongue are involved (M.D. Anderson study reveals 50% of their patients present with stage III or IV disease at presentation) Clinically detected lesions are most often found near the midline area in the anterior floor of mouth. Local extension is typically to the tongue root posteriorly and the anterior gingiva and arch of the mandible. Spread can involve the submandibular ducts, causing obstruction of the gland(s) leading to occasional misdiagnosis of submandibular stone. Spread along the lingual nerve, or the inferior alveolar nerve in the case of mandibular invasion, can lead to skull base involvement. Mandibular involvement occurs as the tumor extends anteriorly in most cases. The mandible is first assessed by evaluating the mobility of the mass; immobility raises the spector mandibular involvement, but can be caused by the gingival adherence to the periosteum, so radiographic studies must be ordered to evaluate the mandible. Bone scans have a high false positive rate (>50%) and are generally not ordered. Despite the wide use of MRI and CT scanning for pre-operative evaluation, it can be difficult to determine whether the mandible is invaded, especially if the patient has dental fillings (distorts CT). One study has bee published showing that a thorough clinical exam yielded more accurate predictions of mandible involvement than either MRI or CT. Statistically, the larger the tumor, the more likely the mandible is to be involved: T % patients with mandibular involvement T1 7 T2 55 T3 63 Significant bone erosion/invasion is usually seen in T4 classification, and is associated with a poor prognosis. The periosteum does provide at least some functional barrier to invasion and as tumor encroaches on the mandible, it frequently invades downward through the mylohyoid to the submandibular space and can involve the submandibular glands, or in advanced cases, the overlying skin. Because of the lack of any real barrier, the cancer can spread easily all the way to the hyoid bone VI RADIOLOGY For all T2 or larger lesions, CT or MRI scanning should be performed pre- endoscopy. Although high resolution CT scans are very useful in evaluating the mandible for possible cortical invasion, MRI is now thought to be as sensitive in the hands of a skilled radiologist. Invasion of the marrow of the mandible is more readily demonstrated by T2 weighted MRI, which suppresses the normally present fat, allowing an intense signal in the event of tumor invasion. Although the combination of T1 and T2 imaging is usually sufficient, a relatively new enhancement called inversion recovery (acronym STIR) allows even more subtle pathologic findings. Recent literature describing a new software program for high resolution CT scanning (Dentascan), states that it is highly accurate and might be superior to conventional CT or MRI imaging in assessing the mandible. This allows imaging of the mandible in cross-section throughout its length in 1 mm slices. MRI is generally superior to CT in evaluating the extent of soft tissue involvement within the oral cavity, or extension to the neck. Nodal involvement assessment by radiological study is helpful, especially in the clinically N0 neck. Many surgeons will "up-stage" a tumor on the basis of suspicious adenopathy seen on MRI or CT. Controversy does exist over the superiority of MRI or CT in this regard. In either case, nodes 1 cm or larger in diameter in levels I & II, and 1.5 cm in lower levels are considered suspicious for metastatic disease. CXR is almost always ordered to help rule out distant metastasis, but the yield of this study is extremely low. Nevertheless, CT of the chest or abdomen is not warranted unless other findings point to the likelihood of distant metastasis. Liver-spleen scans are occasionally ordered in the event liver metastasis is suspected, but CT is considered more sensitive. Ultrasound is also sensitive and less costly. It may be as good as CT when performed by an experienced radiologist. VII STAGING - the AJCC system is used in the U.S. Tx - carcinoma in situ only T1 - lesion is less than 2 cm T2 - lesion is between 2cm and 4cm T3 - greater than 4 cm in greatest dimension T4 - greater than 4 cm with deep invasion to involve the antrum, pterygoid muscles, root of tongue, or skin of neck Nx - unassessable N0 - no clinical adenopathy N1 - single ipsilateral node less than 3 cm N2a - single ipsilateral node between 3 and 6 cm N2b - multiple positive ipsilateral nodes, none largerthan 6 cm N2c - bilateral or contralateral nodes, none largerthan 6 cm N3 - one or more nodes greater than 6 cm Mx - unassessable M0 - no known metastatic disease M1 - distant metastasis present Stage 1 - T1N0 Stage 2 - T2N0 Stage 3 - T3N0, or T1,2,or 3N1 Stage 4 - T4Nany, or TanyN2 or 3, or TanyNanyM1 VIII PROGNOSTIC FACTORS Depth of invasion or "thickness" - illustrates the flaws in the TNM system with regard to prognostic significance. For example, a 4.5 cm superficially infiltrative primary will be designated T3 whereas a deeply infiltrating 2 cm tumor is a T1 lesion but probably carries a worse prognosis. Consistent studies are lacking, but it appears that tumors with a "thickness" of 2-3 mm or greater are statistically correlated to poor prognosis. Cervical metastasis - in general the presence of nodal metastatic disease is ominous, with a survival rate only half of that for patients with similar tumor size and location but without metastasis. Contralateral metastatic nodes carry an even worse prognostic implication. The level at which metastasis occurs also is of prognostic value, with decreasing survival at lower levels. Extracapsular spread - this finding is statistically related to decreased survival and disease free intervals. Some studies show this to be the most important prognostic finding. Mandibular involvement - gross invasion of the mandible with involvement of the marrow is associated with advanced disease and poor prognosis. Microvascular involvement - in the vicinity of the primary, invasion of the microvasculature by tumor carries an increased risk for cervical metastasis TNM Stage - most of the above relate statistically to tumor size, and thus to staging. Although it is not perfect, studies show a strong correlation between stage of disease and outcome. (see RESULTS) Recurrence - either local of neck recurrence are ominous prognostic signs. Salvage survival for neck recurrences are typically no better than 50-60%. Recurrence at both sites in the same patient are associated with an even worse prognosis. IX TREATMENT Stage I lesions are can be treated with equal effectiveness by surgery or primary irradiation; however surgical excision is preferred by most as the morbidity and complications are low with simple wide local excision perorally. Surgical wounds are usually left to heal by secondary intention or covered with skin graft. Typically the neck is not treated in T1 lesions, but some argue it should be. N0 necks, when treated with only observation subsequently develop cervical metastasis 10 - 20% of the time. (see discussion below for more on N0 neck treatment) Stage II lesions are controversial because of the reported relatively high incidence of occult metastasis (up to 40%) associated with T2 lesions. Treatment of the primary lesion can be with surgical excision or irradiation with comparable results by most reports. The controversy centers on the treatment of the clinically negative neck. One can treat the neck with postoperative irradiation, elective or staging neck dissection, therapeutic neck dissection, or simply observe longitudinally. The decision is based on the clinician's judgement, the status of the patient, anatomy (previously irradiated, surgically violated, or thick muscular necks should probably be treated surgically because of the difficulty in clinical assessment), whether the patient is still smoking/drinking etc. (the risk of recurrence and/or second primary is markedly elevated if the patient continues to smoke and drink)., or when the patient is not expected to adhere to follow-up examinations. Advocates of primary irradiation of neck metastasis point to studies showing 90-95% control of neck disease after prophylactic radiation of N0 necks. However, surgical salvage is much more difficult if recurrence does follow radiation therapy. The treatment of the neck and the primary are interrelated in that surgical treatment of the primary is planned if neck dissection is anticipated. Conversely, treatment of the primary affects the neck treatment, as neck dissection is advocated if the primary is to be excised in a mandibulotomy approach (ie - cheek flap), wherein the neck would be entered surgically. If the excision is to peroral, the neck can be treated in whatever fashion is deemed appropriate. There is no controlled study to show improved survival with elective neck treatment. There are a number of retrospective studies that argue for prophylactic neck dissection in Stage II disease. If neck dissection is performed, en bloc continuous FOM/neck dissection is probably advisable. Spiro and Strong reported that discontinuous dissection resulted in no adverse effect on local recurrence or "cure" rate. This has since been refuted in the literature, but remains a point of some controversy. Stage III and stage IV - Although controlled studies are lacking, most authorities agree that advanced SCCA of the oral cavity should be treated with combined surgical and irradiation. Excision of the primary and radical neck dissection of the affected side typically is the treatment regimen. Contralateral neck treatment varies. With palpable contralateral nodes, bilateral neck dissections are carried out but effort should be made to save the internal jugular vein on at least one side if oncologically sound. Most advocate perform at least a contralateral selective neck dissection even in the absence of adenopathy because of the high incidence of bilateral spread in FOM lesions. If microscopic disease is found, irradiation can be given. Alternatively, bilateral comprehensive neck dissections are advocated by some because the recurrence rate in the contralateral N0 neck is about half that of the ipsilateral side. Although theoretically preoperative radiation offers an advantage, results of randomized trials indicate no advantage vs. postoperative radiation, and the rate of serious postoperative complications is markedly higher with preoperative radiation. Indications for postoperative radiation, independent of Stage, would include the discovery of extracapsular spread (even in a clinically N0 neck), close or involved surgical margins, extensive nodal involvement, or intransit soft tissue tumor spread. Treatment of the contralateral neck is not universally agreed upon, but most believe that because of the high incidence of bilateral metastasis, at least the contralateral submandibular triangle nodes should be resected and examined. If they are positive for malignancy by frozen section analysis, the contralateral neck is dissected. Postoperative irradiation usually consists of 6000 - 6500 cGy to the primary and neck(s). Mandibular involvement necessitates surgical treatment. Involvement of the periosteum or very superficial cortical erosion can be treated with marginal mandibulectomy. Advanced cortical involvement, or marrow involvement requires segmental mandibulectomy. The inferior alveolar nerve should always be sampled at the resection margin in mandibulectomies to rule perineural spread. The most likely patient to have invasion of the bone is an edentulous one. X RESULTS 5 - year survival (%) Stage Cummings Suen/Myers (Spiro/Strong) Bailey I 68 88 70 - 85 II 55 80 64 III 28 66 30 - 35 IV 9 32 20 - 25 Recurrence - 90% of recurrences occur within 2 years Overall 33% failure rate in determinate patients 21% @ primary site 37% @ neck 29% @ both 13% distant metastatic disease Surgical salvage is effective approximately 50% of the time ------------------------------------------------------------------------------- BIBLIOGRAPHY Levine P. A., Seidman D. : Neoplasms of the Oral Cavity. In: Bailey B. J., Johnson J. T. 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