Anatomy
Salivary gland tissue is ubiquitous in the submucosa of the upper gastrointestinal tract and is grouped into three major salivary glands: the parotid, the submaxillary (or submandibular), and the sublingual glands. The most common sites of tumors of minor salivary glands are the palate, the base of the tongue, and the buccal mucosa.)

The majority of salivary gland tumors arise in the parotid glands, and although 80% of these are benign, these glands are the origin of the majority of malignant tumors. Tumors arising in the submandibular, sublingual, or minor salivary glands are more likely to be malignant.

The largest salivary glands are the parotids, which are located on the cheeks anterior to the external auditory canal and pinna. The gland wraps around the mandible, and as the facial nerve passes through the parotid, it divides it into superficial or lateral and deep lobes. About 80% of the gland lies lateral to the facial nerve, and 20% lies deep to this nerve and behind and medial to the mandible. The internal carotid artery, the internal jugular vein, the cervical sympathetic chain, and cranial nerves IX, X, and XI are in close proximity to the deep lobe of the parotid.

The lymphatic drainage of parotid tumors is to intraparotid lymph nodes and the upper jugular (levels 2 and 3) lymph nodes. Additional lymphatic drainage is to adjacent levels, including the posterior triangle or level 5. Depending on histology, many nodes may be involved. The presence of nerves within the parotid gland, especially the facial nerve and the auriculotemporal branch of the trigeminal, can be involved by tumors, especially adenoid cystic carcinoma and SCC, which may progress by perineural growth. Any parotid mass warrants exploration, and surgical excision is often the only solution since progression of even benign neoplasms may not only cause facial asymmetry but place the facial nerve at risk.

The second largest glands are the submaxillary (or submandibular) glands, located in the triangle formed by the two bellies of the digastric muscle and the mandible. Malignant tumors in this location can spread to the lymph nodes in levels II, III, and IV, as well as grow along the nerves, preferentially the branches of the lingual nerve and occasionally the mandibular branch of the facial nerve. Seldom will growth occur along the hypoglossal nerve, in spite of the close proximity of the structure. About half of the tumors in the submandibular glands are benign.

The sublingual glands are the smallest of the major salivary glands and are formed off a conglomerate of glands located underneath the mucosa of the floor of the mouth and surrounding the excretory or Wharton duct of the submandibular gland.

Diagnosis
The clinical presentation of malignant salivary gland tumors is variable, depending on the site and histology. The presence of a facial nerve paralysis is uncommon but generally indicates a malignant lesion. Tumors of the deep lobe of the parotid are notorious for producing dysphagia and submucosal deformity of the soft palate. When major invasion of the parapharyngeal space occurs, involvement of cranial nerves IX, X, XI, and even XII can occur. The usual presentation of submandibular gland tumors is a painless swelling below the mandible, and such tumors need to be distinguished from the much more frequent bacterial sialoadenitis of this gland.

On physical examination, a persistent mass without superficial ulceration of either skin or mucosa is the most frequent finding. An important diagnostic procedure to be considered, provided expert cytology opinion is available, is fine-needle aspiration. The objective of this cytologic diagnosis is to rule out neoplasia or confirm the presence of malignancy. This procedure, especially in the parotid and submandibular gland, has gained increasing acceptance and should be considered whenever the information that can be obtained will have an impact on treatment or prognosis. The accurate typing of tumor is often less important and may be deferred to the definitive histologic examination. This has to be applied judiciously in spite of the high accuracy reported by experts (ie, sensitivity, 94%; specificity, 97%; accuracy, 95%).

Histopathology
Benign lesions are the most frequent tumors of the parotid gland. A list of such appears in

Table 90-22.

The basic histologic classification of malignant salivary tumors was developed by Foote and Frazzell (

Table 90-23). Over the years, this classification has been reviewed and expanded to include some less frequently found malignant tumors, and the present WHO classification is most often quoted.

Mucoepidermoid carcinomas constitute about 26%, 21%, and 10% of malignant salivary gland tumors of the palatal, parotid, and submandibular glands, respectively. Mucoepidermoid carcinoma is the most frequent cancer of the parotid gland and is classified into high-grade, intermediate, and low-grade tumors.

Well-differentiated low-grade mucoepidermoid carcinoma is characterized by a slow growth rate, a low recurrence rate after complete surgical excision (about 15%), and rare incidence of metastasis. High-grade tumors are more aggressive, and the local recurrence rate after surgery alone approaches 60%. Local recurrences and distant metastases may occur many years after treatment. About 50% of patients with high-grade mucoepidermoid carcinomas present with regional metastases, and 30% develop metastases at distant sites.

Acinic cell carcinomas are usually well differentiated and account for about 13% of the cancers arising in the parotid glands. Lymph node metastases occur in about 15% of cases. Local recurrence and distant metastases may occur many years after treatment.

Adenoid cystic carcinomas or cylindromas account for approximately 10% of parotid gland cancers and 60% of malignant neoplasms arising in the submandibular or minor salivary glands. An outstanding feature of this neoplasm is its propensity to invade major nerves and spread along the endoneural and perineural sheaths. This has a significant prognostic importance and must be taken into account when designing treatment. Although these tumors often follow an indolent course, as many as 40% of patients ultimately develop regional and distant metastases. Adenocarcinomas account for 10% of parotid gland cancers but are more common in the minor salivary glands. The majority of them are high-grade tumors. About 36% of patients either present with or subsequently develop regional lymph node metastases; therefore, the regional lymph nodes need to be addressed in treatment strategies for adenocarcinomas. Distant metastases to lungs and bone are common.

Carcinoma ex-pleomorphic adenoma arises from preexisting benign pleomorphic adenoma. The risk of malignant transformation increases with time and age of the patient. Of adenomas of less than 5 years’ duration, 1.6% can dedifferentiate; 9.4% of adenomas present for more than 15 years can dedifferentiate. True malignant mixed tumors are very rare, constituting about 2% to 5% of all malignant salivary gland tumors, and are aggressive tumors. The neck nodes become involved in about 25% of patients. In rare instances, a benign-appearing pleomorphic adenoma may produce distant metastases.

Primary SSC of the salivary gland is rare, accounting for less than 3% of parotid neoplasms. It needs to be distinguished from metastatic SCC to the parotid lymph nodes from cutaneous or other origin. SCCs of the skin of the forehead, temple, or ear may metastasize to this region. Such primary sites must be excluded before the diagnosis of primary squamous carcinoma of the parotid can be made. Primary SSCs of the parotid gland may develop regional lymph node metastases in 50% of patients, and this needs to be considered when patients are treated by surgery and postoperative radiation therapy.

Staging
The accepted stagings for salivary gland tumors can be found in the monographs of the AJCC and UICC. Both organizations have agreed to changes bringing the two classifications into agreement. The regional lymph node staging and distant metastasis staging criteria are the same as for the common SCC of the UADT. (

Table 90-24)

The treatment of benign salivary gland tumors is primarily surgical. However, there may be a role for postoperative radiation therapy in situations of incomplete removal or recurrences of benign tumor following prior surgical treatment. If microscopic disease remains overlying the facial nerve, postoperative radiation therapy may be effective in preventing subsequent recurrences.

Surgery is also the primary form of treatment for patients with resectable salivary gland cancer. Early-stage (T1 T2) and especially low-grade tumors should be treated with local excision with free surgical margins. Such tumors arising in the parotid gland are generally treated by parotidectomy with preservation of the facial nerve. Early-stage high-grade tumors of any histology are treated with surgical resection of the primary site, with an attempt to achieve free surgical margins. This often is not possible, and microscopic spread, especially of adenoid cystic carcinoma, may occur along tissue planes, submucosal spaces, and perineural pathways. The dissection of regional lymph nodes should be done judiciously, and elective nodal dissection is seldom indicated. Salivary glands were thought to be resistant to conventional photon radiation, but over the years it has become established that postoperative irradiation is highly effective for eradicating subclinical disease. Postoperative radiation therapy is indicated for major and minor salivary gland cancers when (1) the tumor is high grade or is metastatic SCC, regardless of surgical margins; (2) the surgical margins are close or microscopically positive (which also may include tumors arising in the deep lobe of the parotid gland), regardless of grade; (3) a resection has been performed for a recurring cancer, regardless of the histology or margin status; (4) the tumor has invaded beyond the capsule of the gland into skin, bone, nerve, or glandular tissue; (5) regional lymph nodes contain metastatic cancer; or (6) if there is gross residual or unresectable disease. In addition, preoperative radiotherapy may actually facilitate parotidectomy in advanced cases and allow preservation of the facial nerve.

For T3 and T4 parotid cancer, sacrifice of the facial nerve may be indicated. Unless the facial nerve is circumferentially encompassed by tumor or grossly enlarged by cancer, nerve-sparing surgery may be used followed by radiotherapy. Radiation therapy dosages to the primary site and involved structures are in the range of 5,511 to 6,500 cGy, depending on tumor type and postsurgical status. For low-grade mucoepidermoid carcinomas and acinic cell carcinomas, generally it is not necessary to treat the neck when it is clinically uninvolved. For all other histologies of high-grade, the neck nodal drainage is generally treated to dosages in the range of 5,000 cGy. In the case of adenoid cystic carcinomas, the radiation fields should include the course of significant major named nerve trunks to the base of the skull. A facial nerve that is involved by cancer and still functional preoperatively should be repaired by appropriate resection and grafting. Postoperative radiotherapy can be given to nerve grafts.

Prognosis
The results of treatment depend on both the histologic type and the tumor site. In a series from the M.D. Anderson Cancer Center, 5-year survival rates were 100% for patients with acinic cell carcinoma, 95% for patients with adenoid cystic carcinoma, 90% for patients with low-grade mucoepidermoid carcinoma, 80% for patients with high-grade mucoepidermoid carcinoma, 70% for patients with adenocarcinoma, and 59% for patients with malignant mixed tumors. At the Princess Margaret Hospital, primary parotid disease was controlled by surgery alone in 24% of cases and by surgery and radiotherapy in 74% of cases. In the case of submandibular gland tumors, about half of the patients are free of disease after 5 years, compared with a lesser number of patients with high-grade mucoepidermoid histology. Minor salivary gland tumors, especially tumors in the paranasal sinuses, often present with advanced-stage disease. In an M.D. Anderson series, the t2year local control rate was 47% in patients treated with surgery alone and 76% in patients treated with surgery and postoperative radiation therapy. Results of minor salivary gland tumors are usually more favorable. In selected instances for minor salivary gland tumors, radiotherapy alone might be an option, but local control is less favorable. T stage affects local control of disease, and the extent of disease is more important than the site itself.

Neutron Radiotherapy
For patients with large inoperable salivary gland tumors or for patients that are at high risk for local recurrence after an incomplete resection, fast-neutron radiotherapy is an alternative to standard radiotherapy. Fast neutrons have different radiobiologic properties when compared to standard radiation, and in vivo data from Batterman and colleagues on the response of pulmonary metastases to fractionated radiotherapy shows a relative biologic effectiveness (RBE) factor in the range of 8.0 for salivary gland tumors, compared to RBEs in the range of 3.0 to 3.5 for late effects in most normal tissues. To put this in perspective, if one were to give a dose of 20 neutron-Gy to a parotid tumor, the biologic effect in terms of the mucosa and temporomandibular joint would be equivalent to 60 to 70 photon-Gy, but the biologic effect on the tumor would be equivalent to 160 photon-Gy - a therapeutic gain of 2.3 to 2.6.

The Radiation Therapy Oncology Group (RTOG) in the United States and the Medical Research Council (MRC) in England performed a phase III randomized clinical trial to compare fast-neutron radiotherapy versus conventional photon irradiation for inoperable salivary gland tumors. The fast-neutron group achieved significantly improved tumor clearance at both the primary site and in the regional lymph nodes. At the 2-year endpoint, the local/regional control rates were 67% for the neutron group compared to 17% for the photon group (p < .005), and survivals were 62% for the neutron group compared to 25% for the photon group (p = .1). Because of the significantly greater locoregional control rate achieved in the fast-neutron group, the study was closed early for ethical reasons. Ten-year data continued to show improved locoregional control on the neutron arm (56% vs 17%, p = .009) but no difference in overall survival, due to deaths from distant metastases. A summary of single-institution comparative data is consistent with the results of the randomized trial showing a local control rate of 67% for 309 patients treated with fast neutrons compared to 26% for 298 patients treated with conventional photon irradiation.

Modern neutron treatment facilities allow for three-dimensional conformal approaches to treatment, and this has resulted in further improvement of outcome. Douglas and colleagues reviewed the University of Washington experience involving 148 patients with major salivary gland tumors (mixed histologies). Local control was found to be a function of tumor size, with long-term control being achieved in 78% of patients with tumors smaller than 4 cm compared to 40% for patients with tumors larger than 4 cm. The probability of a patient developing distant metastases was found to be strongly dependent on lymph node status being 52% at 5 years for the node-positive group compared to 32% for the node-negative group. It was found that an initial surgical resection was beneficial in terms of reducing the amount of disease present at the time of neutron radiotherapy.

Another analysis by Douglas and colleagues focused strictly on patients with adenoid cystic histologies. This series consisted of 151 patients with tumors arising in both major and minor salivary glands and who had gross tumor at the time of treatment. The overall 5-year local control rate was 59%, with a 5-year actuarial survival rate of 72%. In patients who had undergone an incomplete surgical resection and in whom there was no skull base involvement by tumor, the local control rate was 80%.

Neutron radiotherapy has also been used to treat patients with multiply-recurrent pleomorphic adenomas. The initial treatment of choice for these benign tumors is surgery, with long-term local control rates being in the range of 95%. However, some patients exhibit multiple recurrences following surgical resection. These cases may present a difficult problem in medical management since further surgery may entail a high risk of damage to the facial nerve. In these situations, neutron radiotherapy offers an alternative form of treatment. The number of patients with multiply-recurrent pleomorphic adenomas treated with fast neutrons is small compared to the number of frankly malignant tumors that have been treated, but results appear quite encouraging. Douglas and colleagues reported on 16 patients who were treated with a median time at risk of 96 months. The 15-year actuarial local control was 76% for patients with gross tumors and 100% for those with only positive minimal disease following their last surgical resection.

Chemotherapy
The local/regional control of disease is only part of the problem in salivary gland tumor management. The incidence of distant metastasis is a function of histology and stage of tumor (

Table 90-25). Distant metastases rates range from 8% for mucoepidermoid carcinoma to as high as 42% for adenoid cystic tumors and high-grade adenocarcinomas. Some of the distant metastases may occur several years after successful treatment of locoregional cancer.

Because of the advent of metastatic disease in high-grade tumors, several phase II chemotherapy studies have been conducted in search of effective systemic therapy for these cases.

Whereas adenoid cystic carcinoma is a slow-growing neoplasm, the mucoepidermoid subtype appears to grow faster and to more closely resemble HNSCC in its biologic and clinical behavior. The single-agent response patterns reflect these differences. Methotrexate can yield a 36% response rate in mucoepidermoid carcinoma. In other histologies, cisplatin combinations with and without doxorubicin (Adriamycin) have been tried, and in the last few years, paclitaxel has proven to be of some benefit in adenocarcinoma and mucoepidermoid carcinoma.

Promising results have been achieved with cisplatin, methotrexate, doxorubicin, vinorelbine, fluorouracil, and paclitaxel. Many of the combination protocols have shown some response, albeit of short duration. A recent study with a dose-intensive cisplatin-based regimen combining all four drugs active in this disease produced a very high toxicity without improvement in response or in survival over single-agent cisplatin or other combinations. Some of the salivary gland tumors may have hormonal receptors, but hormonal therapy based on supportive preclinical work appears to be of limited activity. The taxanes are the most promising new agents under study for salivary gland tumors. New biologic agents are under clinical investigation, and the molecular evaluation of the various tumors may yield new treatment strategies.