The lips are composed of the vermillion or that portion of the lip mucosa that extends from the anterior cutaneous border to the posterior contact area with the opposing lip. The obicularis oris muscle is a subjacent sphincter muscle surrounding the mouth that maintains oral competence. The loosely attached mucous membrane of the oral cavity contains numerous minor salivary glands and is attached to the deep surface of the obicularis oris. In the subjacent connective tissue of the vermilion border, lymphatic channels of the lip begin as a fan of delicate capillaries that merge to form larger connecting vessels. Lymphatics from the upper lip and commissure drain to the ipsilateral preauricular, infraparotid, submandibular, and submental lymph nodes (19). The lymphatics of the lower lip proceed to the submental and submandibular lymph nodes. During embryonic development, the mandibular process fuses in the midline; therefore numerous anastomoses cross the midline allowing drainage to occur bilaterally. Of note, the lower lip lymphatic channels enter the mental foramen of the mandible in approximately 22% of patients (19).
Lip carcinoma is the most common malignant tumor of the oral cavity representing about one-third of these cancers (20). The incidence is approximately 1.8 per 100,000 (20,21). Roughly 90% of the lip carcinomas are squamous cell carcinoma (21). Prolonged exposure to sunlight and having a fair complexion predispose a person to lip carcinoma. Lip cancer is seen most commonly in white male smokers. The majority of lip carcinoma originates near the midline of the exposed vermilion of the lower lip (90%). The oral commissure is the site of origin for 1-6% of lip carcinomas (21,22). Lip cancer is commonly seen in association with primary skin malignancies (21). Often, adjacent to a lip carcinoma, the histologic effects of sun exposure are seen: hyperkeratosis and solar cheilitis (21,23,24). These findings have been reported in association with squamous cell carcinoma of the lip in 46% of patients (23).
Clinically, lip carcinoma presents with a crust on the lip that may bleed upon removal or as a non-healing "blister" which is present for several months. On physical examination, an ulcerated area with surrounding induration is found. The diagnosis is established by an incisional biopsy, which should include part of the deep and lateral margin of the tumor. The deep and lateral margin allows the pathologist to determine the presence of invasive tumor, the pattern of invasion and search for the presence of perineural and lymphovascular invasion. These findings are valuable in the planning of treatment options, evaluating the need for intra-operative frozen section and prognosis.
Due to its prominent location, lip carcinoma can be detected early and is one of the most curable malignancies of the head and neck. Important prognosticators for lip cancer include: size of the tumor, tumor thickness, perineural invasion, and lymph node status (22,24-26). The overall determinate five-year survival rate is 89% (21,23). If left untreated, lip carcinoma will progress to involve skin of the mentum and alveolar mucosa. The mandibular bone may become involved either by direct extension or via lymphovascular or perineural invasion (mental nerve). The perineural invasion may be detected radiographically by unilateral widening of the mental foramen or noted clinically as sensory disturbances (27). Primary lip lesions less than 2 cm have an excellent prognosis with a five-year survival of 90%. Lesions larger than 3 cm, however, have a determinate five-year survival of 64%, and with involvement of the mandible; the five-year survival is less than 50% (21,22). Lip carcinoma recurrences generally increase as the size of the primary tumor increases. The incidence of recurrence is approximately 40% in tumors that are greater than 3 cm in size (22). Those patients with tumors greater than 6 cm have the highest incidence of bilateral lymph node metastasis, and thus have the poorest prognosis (21,26).
Aggressiveness of carcinomas located at the oral commissure is often debated. Generally tumors at this site tend to be larger, therefore increasing the probability of poor prognostic factors such as metastasis, lymphovascular, and perineural invasion.
Investigators who conducted a study involving 46 patients with squamous cell carcinoma at the commissure concluded that the involvement of oral commissure was no more aggressive, but rather, tumors at this location frequently were inadequately resected due to reconstructive considerations (28).
The buccal mucosa extends from the intra-oral surface of the lips in a superior direction to the attachment of mucosa to the maxilla, posteriorly to the mandibular raphae, and inferiorly to the mandibular alveolar ridges. The buccal mucosa is supported by a thin, delicate, loose connective tissue. The buccinator muscle is immediately subjacent to the connective tissue and perforated by the parotid duct.
Although uncommon, squamous cell carcinoma of the buccal mucosa is an aggressive neoplasm of the oral cavity. The reported frequency of squamous cell carcinoma at this site ranges anywhere from 2% to 10% (29,30). The greatest risk factors associated with carcinoma of this site and elsewhere in the oral cavity are smoking and alcohol. In countries such as Asia or India where chewing beetle nut is a common practice, squamous cell carcinomas of the buccal mucosa may constitute approximately 44% of all oral cavity squamous cell carcinomas (31).
Squamous cell carcinoma in the buccal mucosa occurs most often in the sixth and seventh decades of life with the majority of cases being in male patients greater than 40 years of age. The male-to-female ratio ranges from 2:1 to 9:1 in most series (32). In the southeastern and southwestern United States, however, carcinoma of the buccal mucosa is frequently seen in elderly females and attributed to the use of chewing tobacco or snuff (33,34). On the mucosa adjacent to the carcinoma, frequently erythroplasia or leukoplakia can be found (1,2). Invasive carcinoma will generally have one of three clinical growth patterns: exophytic, ulcerative/infiltrative, or a verrucous form. On histologic evaluation, the tumor frequently will have marked infiltration of the lamina propria with deep invasion into musculature may be present (1). The location of the most of these cancers is along or inferior to the plane of occlusion at the middle or posterior aspect of the buccal mucosa (32). Tumors at this site in the early stages are usually completely asymptomatic. As the carcinoma continues to grow, eventually it will become enlarged, traumatized and frequently infected. The tumor can infiltrate the cheek and invade the vicinity of the pterygoid and temporalis muscles, causing trismus. T1 and T2 carcinomas are usually amenable to either surgery or radiation therapy as a single modality (31). Larger tumors (T3, T4) may require excision with cheek flap replacement. Proximity of these lesions to the mandible may require resection of a portion of the mandible. Regardless of the treatment, local recurrences (30-80%) are common (30). Even patients with T1 and T2 tumors that are resected with negative margins (equal to or greater than 5 mm) have 40% local recurrence in some studies (30). Others have shown that combining the T-size of the lesion with tumor thickness (6 mm) has been useful in predicting outcomes (35). The five-year survival for patients of T1 or T2 with less than 6-mm tumor thickness was 98% whereas the corresponding values for T1 or T2 and T3 or T4 that were greater than 6-mm tumor thickness were 65% and 40%, respectively (35). Prognosis is determined by three major factors: the presence/absence of lymph node metastasis, the position of the lesion within the buccal mucosa, and tumor thickness (30,32,35). Generally, the more posterior the lesion is located the poorer the prognosis due to a tendency to invade adjacent structures such as the maxilla, mandible, tonsillar pillars, and soft palate.
The soft tissue that interdigitates between and around the teeth is the free and attached gingiva. Free gingiva forms a collar around the tooth that extends from the gingival margin to the base of the gingival sulcus. The attached gingiva is pink with a stippled surface and, unlike the free gingiva, is tightly bound to the underlying periosteum. The attached gingiva extends from the base of the sulcus to the mucogingival junction, which appears as a scalloped line. The alveolar mucosa is red, smooth, and mobile. The alveolar mucosa covers the edentulous arches in the maxilla and mandible.
Gingival cancer is insidious and frequently masquerades for extended periods of time as a benign inflammatory process such as periodontal disease (36). A number of risk factors have been identified, and include use of tobacco products, alcohol consumption, and probably poor oral hygiene (36). Carcinoma of the gingiva within the United States represents about 4-16% of all oral cancers (37,38). If carcinoma of the lips is excluded, carcinoma of the gingiva is the third most common intra-oral malignancy. This is a disease primarily of the elderly, most often affects the mandibular region over the maxilla and men more frequently than women. Due to the close proximity to the underlying bone, there is usually invasion of the bone early in the course of the disease. Clinical evidence of osseous invasion has been reported to be between 30% and 56% of patients (39). The incidence of osseous invasion appears to be dependent on the proximity of the tumor to adjacent bone and not to the stage of the disease (39). If the tumor reaches the mandibular canal within the mandible, then invasion of the inferior alveolar nerve may result in pain or paraesthesia and possible extension to the skull base (40). There is a particular propensity for nerve involvement in edentulous arches (41).
Two types of bone involvement by tumor have been described: an erosive pattern and a diffuse infiltrative pattern (42). The erosive pattern is a tumor with a pushing border at the bony interface and shows a pattern of resorption at the bony borders of the advancing tumor. In this type of pushing border, there are usually no remnants of bone entrapped within the neoplasm and cancellous spaces are separated from the tumor by a continuous layer of newly formed bone and fibrous tissue. In contrast, the diffuse infiltrative type growth pattern may progress insidiously through the cancellous bone and around neural structures (42). The infiltrative pattern is composed of nests, strands, and cords of tumor cells, which have a tentacular spread along the tumor front (Fig. 1).
Surgery is the preferred treatment for gingival carcinoma and the extent of the surgical procedure is usually determined by the degree and nature of any bony involvement. Those tumors having the erosive pattern of bony involvement may be amenable to conservative procedures. Tumors, however, exhibiting the diffuse infiltrative pattern may require segmental resection of the mandible (42,43).
The erosive pattern of bone invasion has been hypothesized to extend in a more predictable manner than the infiltrative pattern. This non-expansive growth pattern can lead to underestimating the tumor size. The separation of these two distinct his-tological growth patterns has called into question the previously held assumption that mandibular bone invasion universally was a poor prognosticator (42). A recent study evaluated the significance of these two growth patterns and concluded that infiltrative lesions were more likely to result in death with disease or recurrent disease (43). The three-year disease-free survival for the infiltrative pattern and erosive growth pattern was 30% and 73%, respectively. The tumors' with the infiltrative growth pattern in bone more often had primary, regional, and distant recurrence,
and positive surgical margins (soft tissue and bony). Unfortunately, intra-operative and preoperative determination of invasion pattern remains problematic. Intraoperative assessment of bone by frozen section is difficult due to the inherent problems in performing frozen sections on bone. Touch prep of curetted soft bone marrow can be useful for intra-operative evaluation for presence of tumor; however, the histology growth pattern cannot be determined via cytologic touch preparation. Knowledge of the growth pattern intra-operatively may alter the surgical parameters. Post-operative pathologic assessment of the pattern of bony invasion is easily made and provides important reconstructive and prognostic information (43).
The retromolar trigone is a triangular shaped area of attached gingiva overlying the ascending ramus of the mandible. The base of the triangle is from the distal surface of the last molar and the apex terminates superiorly at the maxillary tuberosity. The lateral aspect of this area is continuous with the buccal mucosa and the medial aspect abuts the anterior tonsillar pillars. The mucosa is adherent to the bone. The inferior alveolar nerve and lingual nerves lie just inferior and medial to the mid-point to the retromolar trigone. Tumors involving the retromolar area may penetrate deep into the parapharyngeal soft tissues and extend along the lingual and inferior alveolar nerves ultimately gaining access to the skull base (36,44).
Squamous cell carcinomas of the retromolar trigone occur chiefly in men between 55 years and 70 years of age. Common presenting symptoms are sore throat, otalgia, and trismus. At the time of diagnosis, the majority of tumors are smaller than
4 cm with 27-60% presenting with positive cervical lymph nodes, particularly the submandibular and jugular digastric lymph nodes (36,44-50). Although, the retromolar area is firmly adhered to bone, it has been reported that 14% actually show histologic invasion of the mandible (44). See discussion of bone invasion in alveolar ridge section. T1 and T2 lesions of this area can be affectively treated with radiation or surgery.
The FOM is a crescent-shaped region of mucosa extending from the lingual aspect of the lower alveolar ridge to the interface with ventral surface of the anterior two-thirds of the oral tongue. Posteriorly, the FOM proceeds to the anterior tonsillar pillar, and in the anterior the frenulum of the tongue divides the space into two sides. A sublingual caruncle is on either side of the frenulum anteriorly designating the orifices of the submandibular gland duct (Wharton's duct). Orifices appear as rounded ridges of the mucosa known as the sublingual fold, which overlies the upper border of the sublingual salivary glands. Paired mylohyoid muscles, which act as a muscular diaphragm for the anterior portion of the FOM. The hyoglossus muscle supports the extreme posterior portion of the FOM. The lymphatic vessels of the FOM come from an extensive submucosal plexus. These lymphatic channels drain into ipsilateral and contralateral lymph nodes. Malignancies of the FOM frequently have bilateral metastases.
Squamous cell carcinomas of the FOM are commonly located in the anterior portion near the midline. Carcinomas at this site easily spread to such contiguous structures, such as the alveolar ridge or the ventral aspect of the tongue, or track along the subman-dibular gland duct. Squamous cell carcinoma of the FOM represents approximately 15-20% of all malignant lesions of the oral cavity. If carcinoma of the lips is excluded from the oral cavity, FOM carcinoma is the second most common malignancy only being surpassed by carcinoma of the tongue. Men are affected two to three times as often as women are with this carcinoma. Carcinoma of the FOM in women frequently presents a decade earlier than in men (51), but increased incidence of FOM cancers in women and the margin between the men and women is narrowing (51).
Although any area within the FOM can be affected by carcinoma, the most frequent site of occurrence is the anterior aspect adjacent to the lingual frenulum. Approximately 70% of all FOM tumors occur in this location. The middle third and posterior third of the FOM are roughly split for the remaining 30% (52). The typical initial clinical presentation of FOM carcinoma is that of a non-healing ulcer with or without xerostomia. As neoplasms developing in the anterior FOM advance, they frequently will involve the midline and the papilla of Wharton's duct of the subman-dibular gland. This involvement of Wharton's duct can lead to subsequent obstruction of the salivary gland with ensuing sialadenitis or xerostomia (53). The mucosal borders of these tumors may contain clinically notable leukoplakia or erythroplakia. The deceiving benign appearance and lack of symptoms in these patients may cause early lesions often to be dismissed or misdiagnosed as some inflammatory process. Due to this delay in detection, most lesions in this area at time of diagnosis are greater than 2 cm before the nature of the lesion has been established (53).
Invasion of the mandible at this site has been reported in approximately 15-29% of the patients at the time of diagnosis (39). As with carcinoma of the alveolar ridge and retromolar trigone, proximity to the bone seems to determine this event rather than the size of the carcinoma (42,53).
Several studies have been undertaken to determine predictive tumor features for the likelihood of metastasis to lymph nodes. It appears that tumor stage,
t "«ivi. \ -^i* v\,- r t * J • , t \i •. • \ -'AVv ■
Figure 2 Tumor embolus is seen distending a small lymphovascular structure.
perineural invasion, and intralymphatic tumor emboli (Fig. 2) are often associated with the development of metastasis within the neck. The T-stage, however, in other studies proved to be of little prognostic significance (41,54). Another developing prognostic parameter under investigation is tumor thickness. Some studies have shown that the tumor thicknesses of less than 3 mm correlate with increased survival (55-58). Elective neck dissection for a clinically negative neck for early disease (T1 or T2 lesion) within the FOM is still controversial (59). The growth pattern of T1 and T2 lesions has been analyzed and may be a useful predictor in superficial or microinvasion of the submucosa. The majority of T1 tumors and some T2 tumors tend to grow in a horizontal manner rather than deeply invading the submucosal tissues. If tumors are confined to this horizontal spread without invasion into the submucosa gaining access to larger lymphatic trunks, then tumor dissemination to the cervical lymph nodes is less likely (58). In a recent study of FOM cancers, just looking at tumor size, the incidence of occult metastatic disease was 21% for T1 lesions (59). The importance of "negative" surgical margins (0.5 cm from dysplasia or invasive tumor) has been evaluated several times and the local recurrences have been reported to be 3-32% (60,61).
The tongue is divided into two portions, the anterior two-thirds (oral and mobile tongue) that lies within the oral cavity and the posterior one-third (base of tongue), which is within the confines of the oropharynx. The anterior portion of the tongue, which is in the oral cavity, is arbitrarily divided into four areas: tip, lateral borders, dorsum, and ventral surface (underside adjacent to FOM). Squamous cell carcinoma of the tongue represents approximately 50% of all intra-oral carcinomas. Roughly two-thirds of these carcinomas are located on the mobile aspect of the tongue. The most common site of occurrence for squamous cell carcinoma on the mobile tongue is the lateral border. These lateral border tumors may extend onto the FOM (36). Clinically, squamous cell carcinoma of the tongue most often grows as an ulcerating lesion and can be deeply invasive. The frequency of metastatic disease from carcinoma of the oral tongue is highest for all intra-oral squamous cell carcinoma: 20-40% for T1 lesions; 40% for T2 lesions; 75% for T3 lesions (36).
Squamous cell carcinoma of the mobile tongue can penetrate deeply between the multi-directional tongue muscle fibers and often "skip" to apparently uninvolved areas. The median raphe of the tongue conveys no special resistance to tumor invasion to the contralateral side. The incidence of contralateral or bilateral lymph node metastasis in patients with carcinomas of the tongue is high. Perineural invasion is a frequent finding in these tumors (62). Squamous cell carcinoma of the tongue invades adjacent structures such as the FOM, gingiva, mandible, or base of tongue in roughly 25% of cases (63).
Squamous cell carcinoma of the anterior two-thirds of the tongue tends to be his-tologically well to moderately differentiated tumors. Perineural invasion can be demonstrated in roughly 30% of the cases and is an ominous sign. Approximately 76% of patients with perineural invasion develop positive cervical lymph nodes (Fig. 3) (62,64).
Nodal metastasis is considered to be one of the most common sites of recurrence and treatment failure in tongue carcinoma (65). The predictive value of tumor diameter and T-staging in differentiating the patients with high risk and low risk of nodal metastasis, local recurrence, and survival has been challenged. Recent studies suggest that tumor thickness is a better predictor than T-stage (64) while others have found only perineural invasion to be a significant predictor of patient progression and outcome (66). In one study, tumor-size parameters were evaluated with the use of 3-mm and 9-mm depth of invasion as a division. Tumors up to 3 mm had 10% nodal metastasis, 0% local recurrence, and 100% five-year actual disease-free survival (64). In lesions with tumor thickness more than 3 mm and up to 9 mm, 50% nodal metastasis, 11% local recurrence, and 77% five-year actual disease-free survival was noted; tumors of greater than 9 mm had 65% nodal metastasis, 26% local recurrence, and 60% five-year actual survival (64). Although tumor thickness is currently not a component to the T-stage in the AJCC and UIC TNM staging manuals, as the literature evolves, these parameters may become widely endorsed for evaluation of neck dissections.
A recent epidemiologic observation regarding squamous cell carcinoma of the tongue suggests an increase in occurrence of tumors in patients under the age of 40: squamous cell carcinomas of the tongue increased in patients under the age of 40 from 4% in 1971 to 18% in 1993 (67). More studies are needed to validate this finding.
The palate is divided anatomically into the hard palate, which lies within the oral cavity, and the soft palate, which lies within the oropharynx. The mucosa of the hard palate is located between the horseshoe-shaped maxillary alveolar ridges anteriorly and is attached posteriorly to the ridge of the palatine bone. The mucosa is firmly attached to the periosteum of the underlying bone. The submucosa of the palate
contains more minor salivary glands than any other location within the oral cavity. It is not surprising that this location is particularly prone to salivary gland neoplasms.
In the United States, the hard palate is the rarest site of intra-oral squamous cell carcinoma. The initial lesion usually presents as leukoplakia in about 25% of the cases (68). Half the tumors will be localized to the palate at diagnosis, a third will have extended to adjacent structures, and 15-25% will have metastasized to regional lymph nodes (5% are bilateral) (68).
Although squamous cell carcinoma of the palate is extremely rare in the United States, other types of neoplasms are more frequent at this site. The palate is the most common site for salivary gland malignancies within the oral cavity (69).
The proximity of the greater palatine nerve to a palatal malignancy is noteworthy. Perineural invasion allows tumors to spread in a longitudinal as well as a radial fashion through the planes of least resistance (58). The presence of peri-neural invasion should alert the surgeon and the pathologist to an increased likelihood of perineural extension beyond the confines of the resection margins and extension to the skull base (Fig. 4). This tendency for extension along the nerves is of great significance when planning the treatment of certain tumors (e.g., adenoid cystic carcinoma of salivary gland origin, mucosal, and cutaneous squamous cell carcinomas).
Salivary glands are divided into two groups, major salivary glands (paired); parotid, submandibular, and sublingual, and minor salivary glands of which approximately 300-600 are dispersed within the submucosa of the upper aerodigestive tract. Within the confines of the oral cavity, the major salivary gland group is represented by the submandibular glands and the sublingual glands. Both glands are found in the superficial and deep soft tissue of the FOM. The minor salivary glands are widely distributed throughout the oral cavity but are in greatest concentration within the submucosa of the palate. Anatomically, a major difference between the major salivary glands and minor salivary glands is encapsulation. The major salivary glands have a capsule surrounding them thus defining the borders of the gland. The sublingual gland is the only major gland that may have an incomplete capsule. In contrast, the minor salivary glands are dispersed freely within the submucosa devoid of capsules.
Malignancies of the minor salivary gland represent approximately 10% of all oral cavity cancers and between 10% and 23% of all salivary gland cancers (69). These tumors, due to the diversity of anatomic site and histology, have an unpredictable course and a long natural history. The most common histologic type of tumor in the oral cavity in most series is adenoid cystic carcinoma followed by polymorphous low-grade adenocarcinoma and mucoepidermoid carcinoma (MEC) (70).
Pleomorphic adenomas (PA) represent 50-75% of all salivary gland tumors (71). Intra-orally, the most common sites for PA to occur are the hard palate, lips, and buccal mucosa. Both mesenchyme-like and epithelial elements histologically characterize these tumors. PA of the submandibular and sublingual glands are treated by total glandectomy. When these tumors occur in the minor glands they are excised with the rim of normal tissue (72). Malignant transformation can occur in longstanding PA. In one series of carcinoma expleomorphic adenoma, 18% occurred in minor salivary glands (73). Diagnosis requires the presence or a remnant of pleo-morphic adenoma to be in association with the carcinoma. The extension beyond the capsule has prognostic significance. If confined by the capsular tissue, the carcinoma is called encapsulated, carcinoma in situ or non-invasive carcinoma expleomorphic adenoma (74), and behavior of these lesions is characterized by local recurrence similar to PA.
MEC is the most common salivary gland malignancy. Within the minor salivary gland sites, MEC is most frequent in the palate followed by the buccal mucosa and lips. In the major glands, this tumor presents as a solitary, painless mass frequently associated with obstruction. In the minor glands, the clinical appearance is variable but frequently appears as a blue semi-translucent fluctuant swelling. Symptoms of parathesia, pain, and dysphasia are more often associated with minor gland lesions (75). The tumor is histologically composed of three cells types, mucin-filled globet cells, squamous cells, and intermediate cells. A variety of histologic grading systems exist (71,74). The histologic grade of MEC of the submandibular gland, however, has not correlated well with biologic behavior
Figure 5 Adenoid cystic carcinoma has a distinctive biphasic cellular pattern with a marked propensity for perineural invasion (upper left).
(71,76). Generally clinical stage, histologic grade and adequacy of treatment influence the prognosis.
Adenoid cystic carcinoma (ACC) represents about 8% of carcinoma of all salivary glands. Just under half of the intra-oral ACC occur in the palate. The tumor is composed of two cell types: basaloid myoepithelial cells and intercalated duct-type cells. Tubular, cribriform, and solid architectural growth patterns are recognized. Cribriform growth, with tissue spaces filled with glycoaminoglycans and basal lamina, and extensive perineural invasion are characteristic of this tumor (Fig. 5). The tumor may be circumscribed but frequently frozen section examination of radiating nerve segments will demonstrate the tumor extending beyond the visible borders. Tumors having greater than 30% of the solid growth pattern have a more aggressive clinical course. The solid growth pattern, however, is more often seen in tumors with a high T-stage (77-81). The natural history of this tumor is a long relentless course characterized by late (20 years) recurrences (81).
Polymorphous low-grade adenocarcinoma occurs almost exclusively in the minor salivary glands. In the minor salivary glands, this entity represents 20-25% of all malignant minor salivary gland tumors (71). The tumors are usually circumscribed. There is focal infiltration of the adjacent tissue and notable neurotropism (Fig. 6). This tumor type has a 17% recurrence rate, and about 9% rate of metastases to regional lymph nodes (82). Wide surgical excision for tumor-free margins and long-term follow-up are recommended (71). The vast majority of patients do extremely well following complete excision.
Was this article helpful?
Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.