Epidemiology

Tumors of the major salivary glands are uncommon and account for approximately 2% to 7% of all head and neck neoplasms. In adults, the annual incidence is approximately one to four new cases per 100,000 individuals. The parotid gland is overwhelmingly the most frequent gland affected; cancer in the parotid gland is much more common than submandibular and sublingual gland cancers by a factor of 10 and 100, respectively.

The ratio of benign to malignant tumors varies by site, and there is an inverse relationship between the size of the salivary gland and its incidence of malignancy: (1) parotid gland: 80% benign (primarily pleomorphic adenomas), 20% malignant; (2) submandibular gland: 50% benign, 50% malignant; (3) sublingual gland: less than 40% benign, more than 60% malignant. The average age for benign neoplasms is 40 years, whereas that for malignant tumors is 55 years. The incidence is equivalent for men and women.

The causal factors of these malignant tumors is unknown. The usual risk factors for squamous cell carcinomas of the head and neck—excessive use of tobacco and alcohol—are not clearly proven causal agents for malignant salivary gland tumors. Radiation-induced salivary gland malignancies have been reported in the literature in association with patients who had been irradiated to the head and neck region for benign conditions (e.g., acne, tinea capitis, infected tonsils) and in survivors of the atomic bomb in Hiroshima and Nagasaki. Although an association with female breast cancer has been reported, there is a lack of firm epidemiologic data to support this contention. Nutritional deficiency as a possible cause has been reported in the Arctic Inuit peoples who have a diet low in vitamins A and C. Infection has been cited as a possible cause in whites with the Epstein-Barr virus. Other possible epidemiologic causes include alcohol use, hair dye, and a higher education level.

Anatomy

The major salivary glands comprise the parotid, submandibular, and sublingual salivary glands (Fig. 32-1). Each are paired glands that have different secretory functions: (1) parotid gland—serous; (2) submandibular gland—seromucous; (3) sublingual gland—mucous.

FIGURE 32-1 • The anatomic locations of major salivary glands: parotid, submandibular, sublingual.

(From Spiro JD, Spiro RM: Salivary tumors. In Shah J (ed): Cancer of the head and neck, London, 2001, BC Decker, p 241.)

Parotid Gland

The parotid glands are the largest of the salivary glands (see Fig. 32-1 and Fig. 32-2). These paired glands are surrounded by a discrete capsule and have the following anatomic landmarks: (1) anterior—wraps around the ascending mandibular ramus anterior to the tragus and extends toward the anterior margin of the masseter muscle; (2) posterior—extends from the angle of the mandible under the earlobe toward the mastoid tip; (3) superior—extends to the inferior aspect of the zygoma at the temporomandibular joint level; (4) inferior—extends to the inferior aspect of the angle of the mandible; (5) medial—borders the parapharyngeal-base of skull; (6) lateral—located below the skin of the preauricular cheek–upper neck. The gland is divided into two lobes by the path of the facial nerve, which exits from the stylomastoid foramen (Fig. 32-3): (1) superficial lobe—accounts for 80% of the gland and is located just lateral to the facial nerve; (2) deep lobe—accounts for 20% of the gland and is located medial to the facial nerve and adjacent to the medial aspect of the angle of the mandible and is connected to the superficial lobe by the isthmus (Fig. 32-4). The deep lobe is in close anatomic proximity to the internal carotid artery; the internal jugular vein; the cervical sympathetic chain; and the cranial nerves IX, X, XI, and XII (Table 32-1).

FIGURE 32-2 • Patient with an aggressive malignancy involving the entire parotid gland and the adjacent and regional skin. Note the anatomic delineation of the parotid gland as outlined on this patient.

FIGURE 32-3 • A, Pathway of the facial nerve (cranial nerve VII) as it exits the stylomastoid foramen and then branches out into various anatomic regions. B, Note the presence of the deep lobe of the parotid gland just medial to the facial nerve. C, The facial nerve branches have several distribution variations.

(A from Leblanc A: The cranial nerves, ed 2, Berlin, 1995, Springer-Verlag, p 184. B from Crumley RL, Kelley TF: Rehabilitation of the patient with tumors of the salivary glands. In Thawley SE, Panje WR, Batsakis JG, et al (eds): Comprehensive management of head and neck tumor, vol 2, Philadelphia, 1987, WB Saunders, p 1202. C from Som PM, Curtin HD: Head and neck imaging, ed 3, St Louis, 1996, Mosby, p 829.)

FIGURE 32-4 • Axial view of a noncontrast computed tomography scan of a patient who had previously undergone a right parotid sialogram. Note the superficial lobe, deep lobe, and isthmus of the parotid gland as it wraps around the mandibular ramus.

(From Som PM, Curtin HD: Head and neck imaging, ed 3, St Louis, 1996, Mosby, p 865.)

Table 32-1 The Anatomic Relationship of the Major Salivary Glands and Cranial Nerves

Major Salivary Gland	Adjacent Cranial Nerve	Base of Skull Foramen
Parotid
Superficial/deep lobes	Facial nerve (CN VII)	Stylomastoid foramen
Deep lobe	Glossopharyngeal nerve (CN IX)	Jugular foramen
	Vagus nerve (CN X)	Jugular foramen
	Accessory nerve (CN XI)	Jugular foramen
	Hypoglossal nerve (CN XII)	Hypoglossal canal
Submandibular	Lingual nerve (CNV3)	Foramen ovale
	Facial nerve (CN VII):	Stylomastoid foramen
	Mandibular/cervical branches
	Hypoglossal nerve (CN XII)	Hypoglossal canal
Sublingual	Lingual nerve (CN V3)	Foramen ovale

CN, Cranial nerve.

The parotid gland drains into the oral cavity through the Stensen duct (Fig. 32-5). This duct runs from the upper anterior third of the parotid gland and exits through the buccal mucosa by the second molar. The lymphatic drainage of the parotid gland progresses in an orderly fashion. Initially, it drains into the periparotid (Fig. 32-6) and intraparotid (Fig. 32-7) nodes that comprise two groups located within the fascia of the gland in two respective locations: between the gland and the superficial fascia and within the parenchyma. It then drains into the submandibular nodes (level IB), the upper (level II) and mid (level III) cervical nodes, and sometimes to the retropharyngeal nodes. Drainage to the contralateral nodes is very rare. However, it must be considered if the primary tumor extends across the midline or if there is massive ipsilateral cervical node involvement, which may disrupt the lymphatic pathways and cause spread to the opposite side.

FIGURE 32-5 • Parotid sialogram showing the anatomic location of the gland and the Stensen duct as it exits into the oral cavity by the upper second molar.

(From Som PM, Curtin HD: Head and neck imaging, ed 3, St Louis, 1996, Mosby, p 836.)

FIGURE 32-6 • Periparotid lymph nodes are located on the surface of the superficial lobe but within the fascia.

(From Hoffman H, Funk G, Endres D: Evaluation and surgical treatment of tumors of the salivary glands. In Thawley SE, Panje WR, Batsakis JG, et al (eds): Comprehensive management of head and neck tumors, vol 2, Philadelphia, 1987, WB Saunders, p 1112.)

FIGURE 32-7 • Intraparotid nodes are located within the parenchyma of the gland.

(From Hoffman H, Funk G, Endres D: Evaluation and surgical treatment of tumors of the salivary glands. In Thawley SE, Panje WR, Batsakis JG, et al (eds): Comprehensive management of head and neck tumors, vol 2, Philadelphia, 1987, WB Saunders, p 1112.)

Adjacent to the superficial surface of the parotid gland fascia and anterior to the tragus are the preauricular nodes, which measure less than 3 mm in size and lie within the subcutaneous fat. These lymph nodes receive the lymphatic drainage from the dermis of the upper face, temple of the scalp, eye, nose, and ear. Their involvement is usually associated with skin carcinomas and melanomas in these regions as well as lymphomas. However, primary parotid malignancies do not commonly metastasize to these nodes. Secondary extension into the parotid gland and adjacent facial nerve can sometimes occur. These nodes can then drain into either the inferior parotid nodes (superficial lymph nodes) or into the jugular chain of nodes (level II).

Occasionally, there is an accessory parotid lobe (Fig. 32-8). This lobe has been reported in 21% of normal adult cadavers.¹ However, in a review of 2261 patients with parotid lesions at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1939 and 1978, only 23 patients (1%) had an accessory parotid gland.² Accessory parotid glands are located either cephalad or lateral to the anterior aspect of the Stensen duct and lie over the anterior aspect of the masseter muscle but are separate from the superficial lobe of the parotid gland. Clinically, they are adjacent to the Stensen duct, which is located midway along a line drawn between the tragus of the ear to the lateral upper lip. There can be 1 to 10 tributary ducts from the accessory lobe that will empty into the Stensen duct. This lobe can be clinically significant in that it may be the primary site of a malignant tumor that presents as an asymptomatic swelling in the mid cheek region.

FIGURE 32-8 • A, The accessory parotid lobe is located in the anterior aspect of the Stensen duct. B, Normal parotid gland and the Stensen duct.

(From Johnson FE, Spiro RH: Tumors arising in accessory parotid tissue, Am J Surg 138:242, 1979.)

Submandibular Gland

The submandibular gland (see Fig. 32-1) is 25% of the size of the parotid gland and measures 3 to 4 cm. These paired glands are surrounded by a capsule and are located in the upper anterior triangle of the neck. They are medial to the proximal half of the mandible (Fig. 32-9). The majority of the gland is over the external surface of the mylohyoid muscle, which forms the muscular floor of mouth in the region between the insertion of the muscle and the mandible and which divides the gland into contiguous superficial and deep portions (Fig. 32-10). The posterior aspect is anterior to but near the lower anterior margin of the parotid gland. The inferior aspect can extend caudad a fair distance and approaches the level of the hyoid bone. Of clinical importance is the fact that the submandibular gland is lateral to and abuts the lingual nerve (cranial nerve V3) and hypoglossal nerve (cranial nerve XII) and is medial to the marginal mandibular and cervical branches of the facial nerve (cranial nerve VII) (see Table 32-1).

FIGURE 32-9 • A, Lateral sialogram showing the anatomic location of the submandibular gland and the Wharton duct, which drains into the floor of mouth. B, Anterior sialogram showing the submandibular gland and the medial pathway of the Wharton duct.

(From Som PM, Curtin HD: Head and neck imaging, ed 3, St Louis, 1996, Mosby, p 838.)

FIGURE 32-10 • Anatomic relationships between the submandibular gland and sublingual gland and the adjacent musculature and cranial nerves.

(A and B from Spiro JD, Spiro RM: Salivary tumors. In Shah J (ed): Cancer of the head and neck, London, 2001, BC Decker, p 241.)

The glands drain into the oral cavity through the Wharton duct. This 5-cm duct courses through the niche between the mylohyoid and hypoglossus muscles and emerges in the anterior floor of the mouth toward the midline.

The lymphatic drainage of the submandibular glands progresses in an orderly fashion. Initially it drains into the adjacent submandibular nodes (level IB) as there are no intraglandular parenchymal nodes. It then drains into the upper (level II) and mid (level III) cervical nodes. Drainage to the contralateral nodes is rare.

Benign Tumors

Malignant Tumors

Histopathologic Types

During the past several years, the World Health Organization has expanded its list of suggested histopathologic typing to include a very comprehensive and varied group of malignant tumors:

Acinic cell carcinoma

Mucoepidermoid carcinoma

Adenoid cystic carcinoma

Polymorphous low-grade adenocarcinoma

Epithelial-myoepithelial carcinoma

Basal cell adenocarcinoma

Sebaceous carcinoma

Papillary cystadenocarcinoma

Mucinous adenocarcinoma

Oncocytic carcinoma

Salivary duct carcinoma

Adenocarcinoma

Myoepithelial carcinoma

Carcinoma in pleomorphic adenoma

Squamous cell carcinoma

Small cell carcinoma

Other carcinomas

The relative incidence of the different histologic types according to gland of origin is detailed in Table 32-2.

Table 32-2 Distribution of Histologic Types of Major Salivary Gland Cancer

Type	Percentage
Parotid (n = 1778 cases)
Mucoepidermoid	32
Adenocarcinoma	16
Malignant mixed	14
Adenoid cystic	11
Acinic	11
Undifferentiated and squamous	16
Submandibular (n = 383 cases)
Adenoid cystic	41
Acinic	17
Mucoepidermoid	12
Malignant mixed	10
Undifferentiated	9
Squamous	9
Adenocarcinoma	2

Data from Memorial Sloan-Kettering Cancer Center.¹

Mucoepidermoid Carcinoma

The majority of these cancers are low-grade cancers that tend to be slow-growing, well-circumscribed, and cured by surgery alone. However, some variants are high grades with an aggressive behavior. Mucin production may be absent in high-grade tumors, which are invasive and have an increased risk of spread to lymph nodes (Fig. 32-11). Mucoepidermoid carcinoma is the most common cancer of the parotid gland.³

FIGURE 32-11 • Mucoepidermoid carcinoma. There is no classic microscopic appearance as these salivary gland tumors have a wide variation in cellular composition. A predominance of “epidermoid cells” (closely resemble squamous cell carcinomas that form solid areas and nests) or “intermediate cells” (oval cells that contain a small, darkly staining nucleus), or both, is found.

(Courtesy Andrew Huvos, Memorial Sloan-Kettering Cancer Center Department of Pathology.)

Adenocarcinoma

Most adenocarcinomas are high-grade lesions and are usually associated with minor salivary gland tumors of the oral cavity. There is a propensity for perineural invasion. The risk of lymph node metastasis (30%) and distant spread are significantly increased with the high grade lesions.

Malignant Mixed Tumors

These malignant tumors may arise as a malignant transformation from a benign mixed tumor such as a pleomorphic adenoma. Pathologically, these mixed tumors are described as carcinosarcomas and thus contain both epithelial and mesenchymal components. These are aggressive tumors and are associated with an increased risk of local recurrence (20%) after surgery. They also have a high propensity for lymph node metastasis (>25%).

Carcinoma Ex Pleomorphic Adenoma

These are relatively rare malignancies of salivary glands and account for between 5% and 25% of parotid gland cancers. They arise from pre-existing benign adenomas. Pathologically, they are described as having both a benign lesion such as an adenoma plus a carcinoma. The malignant component is thus epithelial in origin. There is a differentiation of these tumors from malignant mixed tumors in that the latter type has malignant components that are both epithelial and mesenchymal in origin, and is categorized as a carcinosarcoma. These are the most aggressive of malignant salivary gland histologies. The risk of regional nodal metastasis is approximately 20% and such involvement is the most important survival determinant in these tumors.

Adenoid Cystic Carcinoma

This is the predominant malignant histologic type in submandibular and minor salivary gland tumors.³ The appearance (Fig. 32-12) can vary from a cribriform pattern (differentiated) to a mixed cribriform pattern and solid features (moderately differentiated) to solid features (undifferentiated). Some authors have observed that the solid variety can have a more malignant behavior. The natural history can be varied, ranging from a matter of months to 20 years or more. The first evidence of recurrence can be 20 years after diagnosis, making it very difficult to ever determine that an individual patient is cured. Lymph node spread is distinctly uncommon (<5%). Adenoid cystic tumors can cause perineural spread, which may track along the pathways of the cranial nerves to the base of skull. This is important in planning radiation treatment. Many patients (ultimately up to 40%) will develop pulmonary metastases. Because prolonged survival can occur (10 to 20 years) with pulmonary metastases, the primary site must be managed adequately despite the presence of metastatic disease. An example of the management of the primary site in a patient with adenoid cystic cancer and lung metastases is illustrated in Fig. 32-13.

FIGURE 32-12 • Adenoid cystic carcinoma. These are composed of a neoplastic epithelium composed of uniform basaloid cells that contain scant cytoplasm and which are arranged in cords or solid nests. This surrounds a stroma that contains hyaline eosinophilic material or a mucinous myxoid interstitium.

FIGURE 32-13 • A, A 52-year-old woman presented in 1989 with adenoid cystic cancer arising in the parotid gland and metastatic to the lungs. The lung radiograph is seen. B, The primary tumor was partially resected, with gross disease left behind at the facial nerve. To completely resect the cancer would have necessitated facial nerve sacrifice. Using 125I seeds enmeshed in synthetic absorbable sutures, a dose of 22,000 cGy (matched peripheral dose) was delivered. The patient had permanent local control with normal facial nerve function. C, A chest radiograph 4 years later shows progression of the metastatic disease. This emphasizes that adenoid cystic cancer patients can live several years despite lung metastases and should therefore have adequate treatment of the primary tumor.

Acinic Cell Carcinoma

Such lesions are usually found in the parotid gland and represent the second most common malignancy of that major salivary gland. These are typically low-grade and slow-growing malignant tumors. However, they can be locally invasive with involvement of adjacent anatomic structures and thus have a high risk for local recurrence of 30% to 40%. The risk of lymph node metastasis is relatively low, occurring in fewer than 20% of patients. Distant metastasis occurs in fewer than 20% of patients. Late recurrences, both locally and distantly, can develop many years after initial treatment.

Salivary Duct Carcinoma

This type of malignant salivary gland is rare but aggressive. Approximately 27% arise from a pre-existing pleomorphic adenoma. They have a histologic appearance that is similar to infiltrating ductal carcinoma of the breast. Of all the salivary glands, this tumor has a propensity for involvement in the the parotid gland. The clinical course is variable. Locally there is an increased risk for perineural invasion. Regional lymph node metastasis has been found to be as high as 73%. Distant metastasis is a very significant problem and is the most common cause of failure. The prognosis is poor.

Squamous Cell Carcinoma

These are rare but very aggressive tumors. Local invasion of adjacent anatomic structures is typical. There is a very high risk for lymph node metastasis of 50% to 60%. In cases involving the parotid gland, it is important to determine whether the patient has a primary lesion or metastatic disease to the parotid lymph nodes from an adjacent dermal primary site.

Undifferentiated Carcinoma

These lesions are aggressive tumors. Approximately 30% arise from a pre-existing pleomorphic adenoma and are thus a type of carcinoma expleomorphic adenoma. They are associated with a very high risk of lymph node metastasis of 50%.

Special Case: Metastatic Disease from Another Primary Site to Involve the Parotid Gland Region

Occasionally, the parotid gland parenchyma or lymph nodes may be the target site of metastatic disease from another primary site. Three pathophysiologic mechanisms explain such occurrences: (1) lymphatic spread, (2) hematogenous dissemination, and (3) direct extension.

Lymphatic spread to the intraglandular and periglandular parotid lymph nodes can occur from primary skin cancers (e.g., squamous cell carcinomas, melanomas) of the scalp, face, and ears. Occasionally there can be lymphatic spread to the parotid nodes from a primary cancer in the palate, tonsil, or nasopharynx.

The majority of hematogenous disseminations are from primary lung cancers. Other, less frequent primary tumors include tumors of the breast, kidney, and the gastrointestinal tract. Direct extension of malignant disease to the parotid gland can be seen with adjacent osseous sarcomas or overlying skin lesions. Patients who develop metastatic disease to the parotid region from another primary site have a grave prognosis with a poor 5-year survival rate.

Parotid

Submandibular Gland

Sublingual Salivary Gland

Primary Tumor (T) Staging

The T4 stage is still divided into two separate designations as before: T4a and T4b. However, the T4a stage is now described as moderately advanced local disease and the T4b stage is described as very advanced local disease.

The associated stage IV group designations are now as follows: stage IVA (moderately advanced local/regional disease), stage IVB (very advanced local/regional disease), and stage IVC (distant metastatic disease).

Lymph Node (N) Staging

There are two major groups of regional lymph nodes that can occasionally harbor metastatic disease from a parotid gland malignancy that are not specifically addressed in the AJCC cancer staging criteria. They include: (1) peirparotid and intraparotid lymph nodes; (2) ipsilateral retropharyngeal lymph nodes. Their estimated risk of involvement is less than 5%, yet this finding is prognostically important. Metastatic disease to these lymph nodes can be designated as N1 or N2 based on the size of enlargement and the number of lymph nodes involved.¹⁶

Stage Grouping

Major revisions have been made in this area (see Table 32–8).

Additional Descriptors

Lymphatic Vessel Invasion (L) and Venous Invasion (V)

Lymph-vascular invasion not present (absent/not identified)

Lymph-vascular invasion present/identified

Not applicable

Unknown/indeterminate

Surgery

Surgical resection of the involved major salivary gland is the primary treatment of choice. However, patients must be carefully selected to ensure resectability (see “Staging”).

Radiation Therapy

Fast Neutron Therapy

Fast neutron therapy is a specialized form of external-beam radiation. Only a few institutions in the United States have this modality, including the University of Washington in Seattle (Fig. 32-14) and Wayne State University in Detroit.

FIGURE 32-14 • Cyclotron unit delivering fast neutron therapy.

(Courtesy George E. Laramore, University of Washington.)

The therapeutic indications include treatment of primary or locally recurrent major or minor salivary gland malignancies including adenoid cystic carcinomas that have either unresectable disease or partially resected residual gross disease (Table 32-10). The results of fast neutron therapy for malignant salivary gland tumors compared with photon or electron therapy include (1) improved local-regional control, (2) no significant improvement in survival, and (3) greater grade 3 or 4 long-term toxicity with fast neutrons (10%-19%) (Table 32-11).

Table 32-10 Indications for Neutron Therapy in Malignant Salivary Gland Tumors

Primary Disease and Recurrent Disease

• Unresectable gross disease • Partially resectable residual gross disease

Table 32-11 Results of Fast Neutron Therapy in Malignant Salivary Gland Tumors

• Improved local-regional control • No significant improvement in ovarall survival • Grade 3 or 4 long-term toxicity greater with neutrons (10%-19%)

Fast neutrons are a densely ionizing, high linear energy transfer type of particulate radiation that have a limited role in clinical radiation oncology (Fig. 32-15). They are contrasted with photons in the following fashion: (1) the biologic effectiveness of fast neutrons is much less affected by a hypoxic environment; (2) the lethal effects of fast neutrons are less dependent on the cell cycle phase compared with photons; (3) the repair of sublethal damage in malignant cells matters less; (4) fast neutrons are biologically more effective (relative biologic effectiveness [RBE] > 2.6). Also, fast neutrons lack skin sparing and thus can cause a more prominent acute dermal reaction than photons.

FIGURE 32-15 • Fast neutron isodose distributions for treatment of an adenoid cystic carcinoma of a minor salivary gland located in the base of skull: A, Transverse. B, Sagittal. C, Coronal.

(Courtesy George E. Laramore, University of Washington.)

Batterman and associates²¹ measured the RBE of fast neutrons to cobalt-60 for human tumors metastatic to lung. RBE was inferred by observation of growth delay. A metastatic adenoid cystic cancer had an RBE of 8 compared with 2.5 to 4 for most other tumors. This observation on limited clinical material prompted an enthusiastic evaluation of the role of neutrons for the treatment of localized salivary cancers.

Fast neutrons have a high RBE compared with photons. This does not mean, however, that they have a superior therapeutic ratio. Estimates of the exact RBE for salivary cancers are variable and it may simply be that more “radiation effect” was given with the fast neutron doses than with the photon doses. This may have had two effects—one was the increased local control, and the other was the doubling of severe late effects. In the paper from Laramore and associates,²² severe late effects were detailed comparing the two treatments. Severe late effects can be assessed by measuring the occurrence of each category of toxicity in each patient. For photons, there were 10 events in 12 categories of toxicity in 12 patients. This represents a 7% occurrence rate (10/144 = 7%). For fast neutrons, there were 26 events in 12 categories of toxicity in 13 patients, representing a 17% occurrence rate (26/156 = 17%). The outstanding question about fast neutron therapy is whether equivalent local control could be achieved with photons if the dose of photons were escalated to a point at which the toxicity was equivalent to that of fast neutron therapy.

The Radiation Therapy Oncology Group (RTOG; United States) and the Medical Research Council (MRC; England)²² conducted a major randomized phase III multi-institutional clinical trial of the treatment of 32 patients with unresectable salivary gland tumors with either fast neutrons, photons or electrons, or both. The 10-year likelihood of local control was 56% with fast neutrons and 17% with photons and electrons. The fast neutron group had a higher incidence of distant metastasis. The overall survival was not improved with fast neutrons.

Caterall et al.²³ reported on the MRC cyclotron experience of 65 patients with locally advanced or recurrent malignant salivary gland tumors, 89% of which were stage IV, who were treated with fast neutron radiotherapy. They achieved a 72% local control rate. The 5-year survival rate was 50%. The facial nerve was not damaged by fast neutron therapy.

Prott et al.²⁴ reviewed their nonrandomized experience in treating patients with unresectable adenoid cystic carcinoma of the salivary glands using fast neutron therapy. Seventy-two patients were followed for a median of 50 months; 39.1% had a complete remission and 48.6% had a partial remission. The recurrence-free survival was 86% at 1 year, 71% at 2 years and 45% at 5 years. It was concluded that fast neutron therapy for unresectable adenoid cystic carcinoma of the salivary gland was an effective treatment.

Huber et al.²⁵ evaluated and compared their patients with unresectable or partially resectable adenoid cystic carcinoma of major and minor salivary glands that were treated with one of the following approaches: (1) fast neutron therapy, (2) photon therapy, or (3) photon and neutron mixed-beam therapy. The 75 patients in this nonrandomized study were followed for a median of 51 months. The 5-year actuarial local control was as follows: (1) fast neutron therapy: 75%; (2) photon therapy: 32%; (3) photon and neutron mixed-beam therapy: 32%. Postoperative radiation and small tumor size were associated with high local control rates on multivariate analysis. There was no statistically significant difference in overall survival. However, those patients who were treated for primary disease and had negative nodes were associated with improved survival rate on multivariate analysis. Overall acute toxicity was comparable; but there was a higher percentage of grade 3 or 4 late toxicity with fast neutrons (19%) compared with photons (4%) or photon and neutron mixed-beam (10%) therapy. It was concluded that fast neutron therapy could be recommended for unresectable or partially resected adenoid cystic carcinomas of the salivary gland.

Douglas et al.²⁶ reviewed their nonrandomized experience in treating patients with malignant salivary gland tumors using fast neutron therapy. Of 279 evaluable patients, 263 had gross residual disease and 16 patients had no gross disease. There were 141 patients with major salivary gland tumors and 138 patients with minor salivary gland tumors. These patients were followed for a median of 36 months. The 6-year actuarial local-regional control rate was 59%. Patients who had no gross disease enjoyed a 100% 6-year actuarial local-regional control rate. Those patients with a tumor size less than or equal to 4 cm, with no base-of-skull invasion and prior surgical resection but no prior radiation therapy had a statistically significant improvement in local-regional control on a multivariate analysis. The 6-year actuarial cause-specific survival rate was 67%. Those patients with stage I–II disease, minor salivary gland sites, no base-of-skull invasion, and primary disease had a statistically significant improvement in cause-specific survival on multivariate analysis. The 6-year actuarial freedom from metastatic disease was 64%. Those patients without lymph node involvement and no base-of-skull invasion predominated this group. The long-term rate of grade 3 or 4 toxicity was 10%. It was concluded that fast neutron therapy for malignant salivary gland tumors with gross disease resulted in good local-regional control. However, for patients with no gross disease, this treatment resulted in excellent long-term control.

Simulation

Patients undergo simulation in a supine position. The head is placed in a holder that allows hyperextension of the neck. All incisional scars and masses are wired with material appropriate for visualization on regular fluoroscopic simulation films or on the CT scans, depending on which unit is used. A bite block is employed for patients with tumors of the submandibular or sublingual glands; however, it is usually unnecessary for parotid gland tumors. A customized thermoplastic face mask (Fig. 32-16 and Fig. 32-17) or extended head and shoulder immobilizaton unit is created for immobilization and consistency of the head and neck position throughout treatment. A shoulder pull board is employed to bring the shoulder maximally in a caudad direction, particularly when the neck nodes are treated.

FIGURE 32-16 • Customized thermoplastic immobilization face mask and bite block in preparation for computed tomography simulation.

FIGURE 32-17 • Customized thermoplastic immobilization extended head and shoulder immobilization unit and bite block for computed tomogrophy simulation.

At this time, the patient undergoes a fluoroscopically assisted simulation or a CT simulation, depending on whether they will be treated with a two-dimensional or three-dimensional conformal or intensity-modulated radiation therapy (IMRT) treatment plan.³¹

For the patients who undergo a two-dimensional or fluoroscopically assisted simulation, the borders are based on the anatomic structures within the treatment volume that are peculiar to the salivary gland subsite to be treated. Once the simulation films are evaluated and approved, blocks are drawn on them to shield areas not requiring treatment. Cerrobend blocks are then manufactured.

For the patients who undergo a CT simulation (Fig. 32-18), the area within the superior and inferior borders of the field, which includes the treatment volume, are scanned using 3-mm slices. No intravenous contrast is needed. The radiation oncologist then selects the isocenter location on the CT scan, which is then marked on the patient with a permanent tattoo.

FIGURE 32-18 • Computed tomography simulation using head holder, face mask, bite block, and shoulder pull board.

Computer Treatment Planning

The computer data from the CT simulation is downloaded from the CT simulator and transferred to treatment planning computers. The clinical target volume, which represents the visualized tumor (gross target volume) and regions at risk for microscopic disease, such as adjacent tissues or lymph nodes as well as the important adjacent normal structures including the spinal cord, brainstem, optic nerves and chiasm, orbits, cochlea, and the contralateral parotid gland are contoured. When contouring the postoperative surgical bed, the remaining intact contralateral salivary gland is used as an anatomic reference point. A generous margin around the anatomic region of at least 2 cm should be considered to cover the entire operative bed with sufficient borders. For patients who have adenoid cystic carcinoma of the salivary gland, the usual approach is to irradiate the pathways of the adjacent cranial nerve up to the base of the skull. The detailed and complex pathways of the cranial nerve must be carefully and accurately contoured. LeBlanc³² has correlated gross anatomic information with associated CT axial images delineating these pathways. The regional lymph node areas require contouring in specific instances, as noted earlier. Several excellent references are available that explore the anatomic region of the respective surgical lymph node group levels (I to VI) with respect to their location on axial CT slices. Nowak et al.³³ correlated the borders of the surgical levels in the neck (I to VI) with structures seen on a CT scan. They defined the six cervical lymph node regions and noted their respective reproducible landmarks on the CT scan. Wijers et al.³⁴ presented a more simplified approach for delineating cervical nodal target volume based on CT scans. Chao et al.³⁵ published guidelines for target volume determination of head and neck lymph nodes. This was based on their analysis of lymph node failure in IMRT-treated patients. The Danish Head and Neck Cancer Group, the European Organisation for Research and Treatment of Cancer, the Groupe d’Oncologie Radiothérapie Tête Et Cou, and the RTOG consensus guidelines give a very nicely detailed color atlas of CT-based delineation of lymph node levels in the N₀ neck (www.rtog.org.).

This anatomic data is then used for computer-based complex treatment planning employing the three-dimensional conformal radiation therapy (3D-CRT) or IMRT technique, whichever is most appropriate. A thorough discussion between the radiation oncologist and dosimetry staff is held to outline the disease status, treatment goals, areas of concern, and dosage planned. The resulting isodose curves, dose-volume histograms for the tumor area as well as the adjacent critical structures, and the digitally reconstructed radiographs are carefully evaluated (Fig. 32-19, Fig. 32-20, and Fig. 32-21).

FIGURE 32-19 • A 59-year-old man with an unresectable cT₄N_2aM_O poorly differentiated carcinoma of the left parotid gland. He had progressive severe localized pain in the parotid gland and left facial nerve (cranial nerve VII) paralysis. This patient was treated with cisplatin chemotherapy concurrent with accelerated fractionation intensity-modulated radiation therapy–based external-beam radiation therapy with a delayed concomitant boost. The left parotid gland and cervical adenopathy were taken to 70 Gy and the left cervical and supraclavicular nodes were taken to 50 to 54 Gy. A complete clinical response was achieved with resolution of all disease on examination and on computed tomography and positron emission tomography scans. A, Isodose distributions (A1, axial; A2, sagittal; A3, coronal). B, Dose-volume histogram. C, Digitally reconstructed radiographs.

FIGURE 32-20 • A 34-year-old woman with a pT₁N₀M₀ adenoid cystic carcinoma of the right submandibular salivary gland. This patient underwent resection of the gland with pathologic findings of positive surgical margins and perineural invasion. Postoperative intensity-modulated radiation therapy–based external-beam radiation was administered to a treatment volume consisting of the right submandibular gland area and the pathways of the adjacent lingual nerve (cranial nerve [CN] V3) and the hypoglossal nerve (CN XII) to the base of the skull to a dosage of 54 Gy. The postoperative bed in the submandibular area was then boosted to a total cumulative dosage of 63 Gy. A, Isodose distributions (A1, axial; A2, sagittal; A3, coronal). B, Dose-volume histogram.

FIGURE 32-21 • A 34-year-old man with a pT_4BN₀M₀ poorly differentiated mucoepidermoid carcinoma of the left parotid gland (deep lobe) with facial nerve (cranial nerve VII) paralysis. This patient underwent a left total parotidectomy with facial nerve sacrifice. A facial nerve graft with a facial sling was performed. The tumor extended superiorly to the left base of the skull and had completely encased the facial nerve at the stylomastoid foramen. Pathologic evaluation revealed a poorly differentiated mucoepidermoid carcinoma of the left parotid measuring 2 cm, which extended into the periparotid soft tissue and skeletal muscle. The carcinoma focally involved the inked resection margin. There was perineural invasion. All 13 lymph nodes were negative for metastatic disease. The patient was felt to be at high risk for local-regional recurrence, and therefore postoperative radiation therapy was administered to the left parotid gland–left base of the skull, left retropharyngeal nodes–left upper cervical nodes using intensity-modulated radiation therapy–based external-beam radiation therapy to 63 Gy. The ipsilateral cervical and supraclavicular nodes (off spinal cord) were taken to 50 Gy. A, Isodose distributions (A1, axial; A2, sagittal; A3, coronal). B, Dose-volume histogram.

Parotid Gland Tumors

Primary Site

During the past several decades, multiple techniques have been used for the radiation treatment of parotid gland tumors. These have ranged from very basic to extremely complex plans and are related to the evolution of the therapy units, treatment planning sophistication, and our understanding of normal tissue tolerance.

Radiation therapy approaches include (1) electrons—lateral en face electron beam (Fig. 32-22), (2) combination of electrons and photons (50% to 80% weighting toward electrons)—lateral en face electron beam and photons using a direct lateral field or a wedge-pair technique, and (3) photons—wedge pair using 3D-CRT or IMRT approach (see Figs. 32-19 through 32-21).

FIGURE 32-22 • Postoperative left lateral electron beam portal for a parotid gland carcinoma. Note that the dashed line is 1 cm larger than photon portals due to the constriction of the electron isodose lines at depth.

(From Levitt ST, Khan FM, Potish RA, et al (eds): Levitt and Tapley’s technological basis of radiation therapy: practical clinical applications, ed 3, Philadelphia, 1999, Lea & Febiger, p 294.)

The most frequently used techniques have been with a combination of electrons and photons as a so-called mixed beam (Fig. 32-23) or photons alone using a wedge pair (Fig 32-24). Electrons are delivered with a direct lateral en face approach covering the tumor (parotid gland) or tumor bed with a 2- to 3-cm margin (Fig. 32-25).

FIGURE 32-23 • Transverse image of a parotid gland mixed beam (photon and electron) therapy isodose distribution.

(From Perez CA, Brady LW, eds: Principles and practice of radiation oncology, ed 2, Philadelphia, 1998, Lippincott-Raven, p 970.)

FIGURE 32-24 • Transverse image of a parotid gland wedge pair photon beam therapy isodose distribution.

(From Wang CC: Radiation therapy for head and neck neoplasms, ed 3, New York, 1997, Wiley-Liss, p 317.)

FIGURE 32-25 • Transverse image of the electron beam isodose distribution for the parotid gland.

(From Thawley SE, Panje WR, Batsakis JG, et al: Comprehensive management of head and neck tumors, vol 2, ed 2, Philadelphia, 1999, Saunders, p 1190.)

The general portal margins that would encompass the planning target volume are (1) superior—top of the zygomatic bone, (2) inferior—hyoid bone–thyroid notch interspace, (3) anterior—2 cm anterior to the upper second molar, (4) posterior—posterior to the mastoid tip, (5) lateral—2 cm flash of the cheek, and (6) medial—2 cm medial from the ipsilateral oropharyngeal area. However, if the accessory parotid gland is involved with tumor, an additional 2-cm margin must be added anteriorly because this is the location of this parotid gland anatomic variation.

The electron portal margins are 1 cm larger than those for photons because of the constriction of the electron isodose curves at depth. The energy of the electron that is chosen depends on the anatomic distance from the skin of the ipsilateral cheek to the oral mucosa and generally ranges between 12 and 16 meV. In some institutions, the ipsilateral external auditory canal, tympanic membrane, and middle ear are protected from radiation with the use of a Cerrobend ear plug.

The photon technique using a wedge pair involves an anterior and a posterior oblique ipsilateral attack with wedges (45 and 30 degrees) on a cobalt 60 1.25 MV gamma ray unit or a linear accelerator with 4- to 6-MV x-rays. The basic clinical margin setup is similar to that noted previously for electrons but without the added extra 1-cm margin. To avoid an exit dose through the contralateral eye, some practitioners use a slight inferior angulation of the beam. A bolus is placed over the scar if clinically indicated.

When a combination of electrons and photons are used, either modality can start first. There is a weighting between 50% and 80% with electrons, but this can also be with the photon component depending on the discretion of the radiation oncologist. By mixing the two different beams, one can decrease the irradiation of the contralateral parotid gland, acute radiation skin reaction, and mucositis.

With the development of CT simulation and sophisticated computer-based treatment planning, the state of the art and the preferred radiation techniques now mandate the use of 3D-CRT or IMRT depending on the needs and complexity of the plan. For the majority of cases, 3D-CRT using either a two- or three-field approach including wedges is appropriate. However, when the histopathologic anatomy is adenoid cystic carcinoma, the increased risk of perineural invasion and travel along the pathways of the adjacent cranial nerves (beware of perineural skip lesions) require the treatment volume to include the neural pathways to the base of the skull. In such cases, IMRT treatment plans give the best approach.

Sparing the contralateral parotid gland is a very important consideration during the complex treatment planning process for 3D-CRT and IMRT. The dose contraints to the contralateral parotid gland are that (1) the mean dose to the gland should be limited to less than or equal to 26 Gy and (2) the dose to at least 50% of the gland should be limited to less than 30 Gy.

Primary Treatment

The intact, unresectable parotid gland tumor is considered for neutron therapy. In those patients in whom it is elected instead to undergo photon or electron therapy, or both, an accelerated fractionation with a delayed concomitant boost is used often with concurrent chemotherapy using cisplatin (CAP) on days 1 and 22. Initially, with phase I, 1.8 Gy is administered per fraction, one fraction per day, 5 days per week for 4 weeks giving a total dosage of 36 Gy. At this point, phase II begins with twice-a-day treatment separated by at least 6 hours. The morning fraction is a continuation of the initial treatment volume and scheme for phase I for the remaining 2 weeks (10 fractions) to a total of 54 Gy. The afternoon fraction is given 6 hours after the morning dose at a fraction size of 1.6 Gy to a cone-down treatment volume that consists of the primary gross tumor area and adenopathy. This is continued for 2 weeks (10 fractions) to a dosage of 16 Gy. Ultimately, the total cumulative dosage from phase I and II to the gross tumor areas is 70 Gy and to the electively irradiated areas is 54 Gy. The spinal cord dosage is kept to a maximum dosage of 45 Gy.

Primary Site

The bilaterally paired submandibular salivary glands occupy an anatomic location that is adjacent to the medial rim of the mandible from an area just proximal to the angle of the mandible to the mid aspect of the mandible in the mid to lateral floor of mouth region. The superior extent of the gland is below the mucosa of the lateral floor of mouth region. The inferior extent of the gland approaches the hyoid bone.

The general portal margins that would encompass the planning target volume are (1) superior—1 cm above the upper border of the tongue, (2) inferior—hyoid bone–thyroid notch interspace, (3) anterior—anterior aspect of the mental symphysis, (4) posterior—base of tongue–jugulodigastric nodal area, (5) lateral—2 cm flash of ipsilateral mandible, and (6) medial—midline of tongue.

The radiation therapy techniques for the parotid gland tumors are applicable to this region. Generally, a combination of electrons and photons or photons alone have been used. However, treatment planning with 3D-CRT or IMRT for photons represents the best contemporary treatment approach. This allows a carefully sculpted homogenous dose delivery to the tumor area and good sparing of adjacent structures.

Lymph Nodes

The submandibular salivary glands drain in an orderly fashion to the adjacent submandibular nodes (level I) and then into the upper (level II) and mid (level III) cervical nodes. Contralaterally, lymph node drainage is rare.

The indications for irradiation of the ipsilateral regional lymph nodes are the same as for parotid gland tumors. However, there is up to a 30% incidence of lymph node metastasis in general and some practitioners always include irradiation of the lymph nodes when the primary area is treated.

The treatment volume includes the ipsilateral submandibular, cervical, and supraclavicular nodes. The field arrangements are similar to those used for parotid gland tumors.

Radiation Dosage

The treatment approaches and dose guidelines for parotid gland tumors are applicable for submandibular gland tumors.

Primary Site

To treat the sublingual gland region, the general portal margins that encompass the planning target volume are as follows: (1) superior—1 cm above the upper border of the tongue, (2) inferior—hyoid bone–thyroid notch interspace, (3) anterior—anterior aspect of the mental symphysis, (4) posterior—posterior aspect of the ascending mandibular ramus, (5) lateral—2-cm flash of ipsilateral mandible, and (6) medial—2 cm past midline (however, the entire floor of mouth–submental region usually requires treatment).

Right and left opposed lateral portals are needed to completely encompass this treatment volume, particularly when the regional lymph nodes are included. IMRT or 3D-CRT complex treatment planning may be indicated when only the primary tumor area is treated with radiation therapy, as this approach may improve sparing of adjacent structures.

Lymph Nodes

The sentinel nodes are the submental and submandibular nodes. From there, the lymphatic drainage is to the cervical chain and to the supraclavicular nodes in an orderly, predictable fashion. Because of the potential for contralateral lymphatic spread of sublingual gland tumors resulting from their lateral to mid-line anatomic location, the bilateral nodes must be treated.

The indications for irradiation of the regional lymph nodes are the same as for parotid gland tumors.

Radiation Dosage

The treatment approaches and dose guidelines for parotid gland tumors are applicable for sublingual salivary gland tumors.

Critical Normal Tissues: Radiation Injury

Acute and Late Side Effects

Accessory Parotid Gland Tumors

Treatment approaches are similar to those for parotid gland malignancies with surgery as the initial treatment of choice. A standard parotidectomy incision is used with an anterior extension superiorly. Once the lesion is exposed and evaluated and malignancy is confirmed, a wide local excision is performed for localized mobile lesions without extension to the main parotid gland. Such limited surgery alone for these selected lesions is generally curative. The role for postoperative radiation therapy is similar to that for the main parotid gland.

Adenoid Cystic Carcinoma (Cylindroma)

Adenoid cystic carcinoma is a relatively uncommon pathologic subtype comprising approximately 2% to 5% of salivary gland malignancies. It affects men and women equally and is the most common malignant tumor of the minor salivary glands and submandibular.

The initial treatment of choice for adenoid cystic carcinoma is surgical resection. However, it should be noted that this type of malignancy has the propensity not only for perineural spread, but also for insidious local extension, both of which can make it difficult to surgically encompass the potentially involved region adequately. Thus, postoperative radiation therapy is recommended. The routine use of combined surgery and postoperative radiation therapy has been associated with improved local control for both major and minor salivary gland adenoid cystic carcinomas.

There is a 50% incidence of microscopic perineural invasion, particularly of the adjacent cranial nerves. Perineural spread can be associated with skip areas of involvement and therefore one cannot be comfortable with negative neural margins on frozen section. Thus, postoperative radiation therapy of the entire pathway of the adjacent cranial nerve to the base of the skull is employed. The resultant base-of-skull failure from perineural invasion and extension of adenoid cystic carcinoma is associated with significant morbidity and is very difficult to treat effectively. Garden et al.⁴⁵ found that the base-of-skull failure was rare whether or not elective radiation was given to the skull base. The policy at MSKCC, however, is to irradiate the adjacent cranial nerve pathway to the base of the skull in all patients who have adenoid cystic carcinoma of the salivary gland (see Fig. 32-20).

The overall incidence of regional lymph node metastasis at presentation is 15%. Because the risk for occult nodal metastasis is rare, elective surgical dissection or irradiation is not employed.

Spiro and Huvos reviewed the MSKCC experience of 184 previously untreated patients with adenoid cystic carcinoma of the minor and major salivary glands.⁴⁶ Of these, 63% were stage I or II, 43% stage III, and 21% stage IV. Sixty-eight percent were grade 1 (cribriform pattern only), 26% were grade 2 (mixed cribriform pattern and solid features), and only 5% were grade 3 (solid only). All patients were treated with surgery but relatively few received postoperative radiation therapy. The cumulative 10-year survival rate was as follows: (1) stage I/II, 75%; (2) stage III, 43%; and (3) stage IV, 15%. The cause-specific survival at 10 years was 94% for stage I. They arrived at two important conclusions: (1) The clinical stage was the only factor that had significant effect on survival, and (2) the tumor grade alone was not predictive of survival, regional nodal metastasis, or distant metastasis. Surgery alone has been associated with a local control rate of 25% to 40%; however, when postoperative radiation therapy is employed, local control rates increase 75% to 80%.

Of recurrences from salivary gland malignancies, 70% occur generally within the first 2 years of treatment. However, with adenoid cystic carcinomas, most of these local failures occur much later. These patients must be followed closely for many years post-treatment.

Adenoid cystic carcinomas can have a natural history of several years even when presenting with metastatic disease. Consideration of controlling the primary tumor is prudent (see Fig. 32-13).

Recurrent Major Salivary Gland Cancers

Surgery is the treatment of choice for locally recurrent major salivary gland cancers. To maximize the chances of resectability and control, recurrent lesions must be diagnosed as early as possible. Thus, close follow-up is mandatory for the first 2 to 3 years after the initial treatment.

Unresectable, previously unirradiated, locally recurrent disease can be considered for concurrent chemotherapy and accelerated fractionation external-beam radiation therapy if neutron therapy is not a viable option. Brachytherapy can be considered in selected cases.

The role of postoperative radiotherapy in patients with local recurrence who did not receive radiation as part of their initial treatment is not clear. In patients with resected large recurrent tumors and high risk features, postoperative external-beam radiation should be considered. Brachytherapy can also be used in selected cases.

Armstrong and associates⁴⁷ reviewed the experience at MSKCC of recurrent major salivary gland malignancies in 78 patients who underwent resection of locally confined recurrent major salivary gland cancers. Thirty-eight patients had completely resected tumors, with low- or intermediate-grade histologic anatomy, without lymph node spread, and the cause-specific survival rate was 83% at 5 years, 70% at 10 years, and 48% at 15 years. Local control for these 38 patients was superior for those with tumors of 3 cm or less compared with those with larger tumors: 80% versus 62% at 5 years, and 73% versus 25% at 10 years (P < 0.05).

The remaining 40 patients had high-risk features (high-grade histologic anatomy, lymph node metastases, and close or positive margins of resection). Half of the high-risk patients received postoperative radiation therapy and half did not because radiation had been given before the development of local recurrence. Consequently, although local control was enhanced with radiation, this analysis could not determine the role of postoperative radiation. However, the data indicate that surgery alone yielded good local control in patients with small tumors (<3 cm) and no high-risk features, suggesting that postoperative radiation may be unnecessary for these patients if they can be closely followed.

However, another study by Spiro and Spiro at MSKCC reviewed the results of attempted salvage of patients developing locally confined recurrences following initial therapy of their primary tumor.⁴⁸ Between 1966 and 1982, 155 patients presented with locally confined new primary carcinomas and were treated surgically with or without radiation therapy.⁴⁸ Of the latter group, local failure occurred in 15% (23/155) and only 7 of the 23 were suitable for salvage surgical therapy. All but one of the seven died of their disease, with an actuarial survival rate of only 21% 5 years after recurrence.^48a In an attempt to explain this discrepancy, it has been postulated that the extent or completeness of therapy administered at the time of the initial diagnosis, before the development of a recurrence, may be an important predictor of the success of management of locally recurrent salivary cancer. The mechanisms of local recurrence following minimal or inadequate initial therapy may differ from the mechanisms of recurrence following aggressive initial therapy. The former may be related to technical factors, whereas the latter may be a manifestation of biologic aggressiveness.

Few other data address the role of postoperative conventional external-beam radiotherapy in the management of recurrent tumors of the major salivary glands. Guillamondejui and associates⁴⁹ from the MD Anderson Hospital treated 12 patients with surgery or radiotherapy or both for locoregional recurrences. Locoregional control was achieved in 42% (5/12). In contrast, King and Fletcher,⁵⁰ from the same institution, reported a crude locoregional control rate of 81% (25/31), with minimum follow-up of 2 years, among patients presenting with postoperative local recurrences treated with radiotherapy. Tu and associates,⁵¹ from the Chinese Academy of Medical Sciences, reported a significant survival advantage with the use of postoperative radiotherapy for recurrent parotid cancers. At 5 years, 89% of the patients (17/19) were alive in the combined-therapy arm compared with 59% (10/17) in the surgery-alone arm.⁵² This paper did not compare prognostic factors between the two groups, nor did it detail the patterns of treatment failure. In addition, as the numbers of patients were small, it is difficult to make firm conclusions as to the efficacy of postoperative radiation therapy.

Armstrong and associates reported on 20 patients with recurrent¹⁹ or advanced¹² disease who were treated with 192Ir and 125I brachytherapy as described earlier.¹⁹ Previous radiation therapy had been administered to 15 patients. The implant was to gross disease in 15 of the 20 patients. Actuarial local control was 60% at 5 years. Two patients had soft tissue necrosis as a complication, which was resolved with conservative management. There were two cerebral abscesses, one of which was fatal. Both patients had extensive skull-base tumors treated with partial resection and 125I brachytherapy for gross residual disease.

Brachytherapy can be used in conjunction with resection if the resection margins are close or positive, or in the presence of a T₄ tumor. It may also be used as sole treatment of accessible localized recurrent disease previously treated with radiation therapy. Permanent 125I seeds can be implanted directly into the tumor or embedded in a synthetic absorbable suture and sewn into tumor beds. The typical matched peripheral dose for 125I implants is 160 Gy. Afterloaded 192Ir can be used as a temporary implant in single or multiple planes for either microscopic residual disease or unresected disease. Typical median peripheral doses are 45 Gy for microscopic disease and 60 Gy for gross disease. A patient with a resectable submandibular cancer with lung metastases who was treated with 125I is illustrated in Fig. 32-26.

FIGURE 32-26 • An elderly patient with a submandibular malignant mixed tumor. The patient had lung metastases. A, Computed tomography (CT) scan showing a left submandibular cancer, which was not resected. B, The procedure using Mick afterloading needles to implant 125I seeds into the tumor. One hand is kept in the mouth to guide the needles as they are being implanted. C, Localization films with the seeds in place. D, A CT scan showing the 125I seeds well localized in the tumor. The matched peripheral dose was 16,000 cGy. Local control was achieved for the duration of survival (1 year).

Pleomorphic Adenoma (Benign Mixed Tumor)

Pleomorphic adenomas are benign tumors of salivary glands, but they can also occur in lacrimal glands. The pleomorphic adenoma is the most common benign tumor of the parotid glands and accounts for 75% of all parotid epithelial tumors. These adenomas occur rather frequently and generally are found in a relatively young population.

The initial treatment of choice is excision of the tumor with a margin of normal tissue with preservation of the facial nerve. Simple enucleation of the tumor is contraindicated. The likelihood of local recurrence for most patients who undergo uncomplicated surgery is only 1%. The few cases that have local postoperative recurrences can generally be treated again with surgery. However, multiple recurrent tumors carry up to a 25% risk for further recurrences. With each recurrence, the probability of malignant transformation (e.g., carcinoma ex pleomorphic adenoma) or facial nerve damage increases.

Pleomorphic adenomas are radioresponsive tumors. In selected cases that are at high risk for local recurrence, the use of postoperative radiation therapy is associated with a cumulative risk of recurrence of 8% at 20 years.⁵³

There is an established role for the use of radiation therapy in this benign lesion.^54–58 The indications for postoperative radiation therapy include (1) more than three histologically benign local recurrences, with each recurrence associated with an increasing degree of infiltration; (2) a large lesion (>3 to 5 cm) for which surgery is associated with inadequate margins; (3) microscopically positive surgical margins; (4) macroscopic residual disease; and (5) malignant transformation⁵⁴ (Table 32-16). Previously, postoperative radiation therapy was indicated if there was tumor spill during surgery, but now this is not felt to be the case.^58a

Table 32-16 Indications for Postoperative Radiation Therapy for Pleomorphic Adenomas

The use of postoperative radiation therapy must be based on selective and judicious indications, as noted earlier, as well as astute clinical judgment. Despite its effectiveness in controlling pleomorphic adenomas, its liberal administration is contraindicated. Because these lesions are benign and are usually found in young patients, the exposure of such patients to the small but definite risk of developing a radiation-induced malignancy as a late complication is unjustified.

The radiation oncology technical approaches are as presented previously for malignant tumors of the salivary gland. Because this is a benign lesion, there is no attempt to include the regional lymph nodes. However, when malignant transformation is noted in a recurrent lesion, the technique chosen is identical to that for a similar malignant lesion of the salivary gland.

The total cumulative dosage of radiation therapy that is administered for pleomorphic adenomas is 50 to 60 Gy depending on the particular surgical and pathologic characteristics of the case.

Epidemiology

Although tumors of the major salivary glands are uncommon and account for approximately 3% to 4% of all head and neck cancers, the minor salivary gland tumors are rare. They account for 7% to 10% of all salivary gland tumors. Minor salivary gland tumors can occur at any age. However, they are rare in children younger than the age of 10 and uncommon before the age of 20 years. The causal factors of malignant minor salivary gland tumors are unknown. The possible causes have been discussed previously for the major salivary gland tumors.

Anatomy

The minor salivary gland tumors involve small, predominantly mucus-secreting glands located beneath the mucosal lining of the upper aerodigestive tract. The highest concentrations of these glands are located in the oral cavity, palate, nasal cavity, and paranasal sinuses. There are approximately 500 to 700 such glands. It should be noted that no minor salivary glands are located in the gingivae or anterior half of the hard palate. Aberrant salivary tissue has been reported in many differing and diverse sites—a lymph node, middle ear, or even the sternoclavicular joint, to name a few.

Pathologic Conditions

Approximately 50% of minor salivary gland tumors are malignant. The histopathologic presentations include adenoid cystic carcinoma, mucoepidermoid carcinoma, adenocarcinoma, carcinoma in pleomorphic adenoma, acinic cell carcinoma, and oncocytic carcinoma.

In general adenoid cystic carcinoma is the most-often encountered malignant minor salivary gland tumor. However, adenocarcinoma is most common in the nasal cavity and paranasal sinuses,¹¹ whereas mucoepidermoid carcinoma is highest in the oropharyngeal region, particularly in the base of tongue.⁵⁹

The most frequently encountered benign tumor of the minor salivary glands is the pleomorphic adenoma.

Clinical Presentation and Evaluation

Staging

Minor salivary gland malignancies are staged using the AJCC TNM criteria for squamous cell carcinomas associated with the site of the primary lesion.

Treatment

Side Effects

The specific side effects associated with radiation therapy for minor salivary gland malignancies depend on the anatomic site of the primary, whether the regional lymph nodes need to be included in the field, the cumulative dosage of radiation administered, and the radiation technique employed. In general, the radiation side effects presented previously for the major salivary gland malignancies are applicable to minor salivary gland tumors. However, because of the increased frequency in the use of right and lateral opposed portals, particularly for oral cavity and oropharyngeal lesions, the degree of xerostomia, loss of taste, and mucositis may be more significant.