Salivary Gland Neoplasms Treatment & Management
- Author: Steve C Lee, MD, PhD; Chief Editor: Arlen D Meyers, MD, MBA more...
In general, salivary gland neoplasms respond poorly to chemotherapy, and adjuvant chemotherapy is currently indicated only for palliation. Doxorubicin- and platinum-based agents are most commonly used with the platinum-based agents that induce apoptosis versus the doxorubicin-based drugs that promote cell arrest. Platinum-based agents, in combination with mitoxantrone or vinorelbine, are also effective in controlling recurrent salivary gland malignancy. A new form of 5-fluorouracil called fluoropyrimidine that has increased activity against malignant cells and while having fewer gastrointestinal side effects has shown to be efficacious against malignant salivary cancers and to potentiate the effects of radiotherapy by increasing apoptosis.
Newer trials with antimicrotubule agents with and without concomitant radiotherapy have shown efficacy. Using a platinum-based agent, cisplatin, and an antimicrotubule drug, docetaxel, with radiation shows some promise in advanced carcinomas of the salivary gland. Using paclitaxel (Taxol), another antimicrotubule drug, alone has had moderate activity against mucoepidermoid tumors and adenocarcinomas but no effect adenoid cystic carcinoma.
Various targeted biologic agents such as trastuzumab, imatinib, and cetuximab are currently being investigated.
Radiotherapy is still not considered to be the criterion standard after surgical resection of salivary gland neoplasms; however, it is used alone for tumors that are considered nonresectable. More studies have quantified the use of radiotherapy in the postoperative setting. The use of radiation in T1 and T2 parotid gland tumors found that 5-year disease-free survival increased from 70% to 92% with postoperative radiation. A second study investigated postresection radiotherapy for carcinoma ex pleomorphic adenoma and found a 26% improvement in 5-year local control (from 49% to 75%). Nonetheless, prospective randomized controlled studies are needed to confirm the usefulness of postoperative radiotherapy.
Newer techniques for postoperative radiation in salivary gland malignancies have been proven effective. These include gamma-knife stereotactic radiosurgery and brachytherapy (radioactive seeds or sources are placed in or near the tumor itself, giving a high radiation dose to the tumor while reducing the radiation exposure in the surrounding healthy tissues). Iodine-125 seeds have been found to be an effective treatment for incompletely resected or unfavorable histological salivary gland malignancies of the hard and soft palate. Gamma-knife treatments after neutron therapy are useful if the local failure risk is still high.
Recent reports have shown that neutron-based radiation therapy may be more effective than photon-based radiation therapy for the treatment of malignant salivary gland neoplasms with gross disease and provides excellent local and regional control of microscopic disease. This therapy has been proven to have good local control and survival rates in patients with grossly recurrent pleomorphic adenomas that cannot be resected. In adenoid cystic carcinoma that is recurrent, is advanced, or has been resected with positive margins, neutron therapy can provide better local control than photon-based therapies, but it does not improve survival because of the excessive number of metastases that prevail in advanced stages. Doses as high as of 60 Gy (1 Gy=100 rad) were needed in stage 3 or 4 tumors that have invaded bone, nerves, or lymph nodes. If the tumor is completely unresectable, doses as high as 66 Gy are needed.
Carefully planned and executed surgical excision is the primary treatment for all primary salivary gland tumors. The principles of surgery vary with the site of origin and are discussed as such.
Superficial parotidectomy with identification and dissection of the facial nerve is the minimum operation for diagnosis and treatment of parotid masses. Neither incisional biopsy nor enucleation should be performed for parotid masses.
Surgery is the primary treatment of malignant tumors of the salivary glands. This is often combined with postoperative radiation therapy, depending on the specific tumor characteristics and stage. The extent of surgery is based on the size of the tumor, local extension, and neck metastases. The facial nerve is spared unless it is directly involved. Radiation therapy is recommended for all but small low-grade tumors.
The histopathologic diagnosis of parotid masses is often unknown prior to surgery. Thus, the minimum procedure that should be performed for masses in the parotid gland is a superficial parotidectomy with identification and preservation of the facial nerve. The shift from enucleation, which was popular prior to 1950, to superficial parotidectomy as the minimal procedure for parotid tumors has substantially reduced recurrence rates for both benign and malignant disease. For benign pathology, this procedure is curative. By today's standards, enucleation with incisional biopsies should never be performed.
The specimen removed by superficial parotidectomy should be sent to the pathology department for frozen section analysis to intraoperatively determine whether a lesion is benign or malignant. Malignant diagnoses deserve special consideration.
The facial nerve should not be sacrificed for benign tumors.
On the basis of the histologic classification and clinical stage, a useful management schema has been developed and is shown in the Further Reading section.
Four groups are identified. (Tumor, nodes, and metastases [TNM] stages are described in Staging.)
Group 1 includes T1 and T2 low-grade tumors (eg, low-grade mucoepidermoid carcinoma, acinic cell carcinoma). For these tumors, perform parotidectomy (superficial or total) with an adequate margin of normal tissue with preservation of the facial nerve. Inspect first-echelon nodes at the time of surgery and send suspicious nodes to the pathology department for evaluation. For complete excision without tumor spillage and no evidence of cervical metastases, radiation therapy is not performed.
Group 2 includes T1 and T2 tumors with high-grade features (eg, high-grade mucoepidermoid carcinoma, adenoid cystic carcinoma, squamous cell carcinoma, adenocarcinoma, carcinoma ex-pleomorphic adenoma). For these tumors, perform total parotidectomy, including the first-echelon lymph nodes. Perform further neck dissection (modified radical neck dissection or selective neck dissection) for upper nodes confirmed to be positive for malignancy on frozen sections or for clinically palpable cervical disease. Preserve the facial nerve unless it is directly infiltrated by tumor. In this case, the nerve is resected until the frozen section shows clear margins, and it is immediately reconstructed with cable grafting. Administer postoperative radiation therapy to the parotid region and the neck.
Group 3 includes any T3 tumor, any N+, and any recurrent tumors not in group 4. Tumors in this group generally require radical parotidectomy with sacrifice of the facial nerve in order to obtain sufficient tumor-free margins. Perform frozen sectioning of the facial nerve stump with continued excision until the margin is free. Immediately reconstruct the facial nerve with a cable graft. Perform neck dissection for positive nodal disease and treat the parotid bed and neck with postoperative radiation therapy.
Group 4 includes T4 tumors. Direct excision is performed based on tumor size and location. Perform radical parotidectomy with excision of the involved structures (eg, facial nerve, mandible, mastoid tip, skin) as required to obtain tumor-free margins. Complex reconstruction, including free tissue transfer, is usually required to maximize functional restoration. Perform neck dissection for N+ disease and administer postoperative radiation therapy.
Routine fine needle aspiration biopsy (FNAB) for submandibular masses is helpful to rule out inflammatory disease of the submandibular gland, which is treated nonoperatively, and to rule out metastatic disease to the submandibular region, which is treated on the basis of the primary neoplasm.
Benign neoplasms of the submandibular gland require complete excision of the gland. Malignant neoplasms at a minimum require complete excision of the gland plus extended surgery, depending on the specific tumor factors.
Submandibular salivary gland malignancies may be treated with a similar approach as parotid gland malignancies. For small, low-grade tumors (group 1), submandibular triangle excision is adequate without resection of cranial nerves.
For group 2 tumors, a wider resection of the submandibular triangle is required for clear margins. Sacrifice nerves only if they are directly involved with a tumor. Frozen-section sampling of the epineurium of cranial nerves near the tumor mass may be performed, with the results directing further excision. Perform neck dissection for clinically positive disease. Postoperative radiation therapy is given.
Group 3 tumors commonly require sacrifice of the lingual and hypoglossal nerves to obtain clear margins. Perform selective or modified radical neck dissection and administer postoperative radiation therapy.
Group 4 tumors require wide surgical extirpation to fit the tumor extent. This may include mandible, floor of mouth, tongue, skin, and cranial nerves with appropriate reconstruction. Neck dissection and postoperative radiation therapy are added for these tumors.
Perform surgery with the patient under general anesthesia without paralysis. The face and neck are exposed and should be draped to allow visualization of facial motion throughout the case. A properly designed incision allows adequate exposure and yields a good cosmetic result. An incision is made in the preauricular crease. The incision may be extended posterior to the tragus. The incision is extended to the attachment of the lobule and carried over the mastoid tip, then extended into the neck in a skin crease. Alternatively, a facelift incision may be used for hidden scar placement in the hairline.
Elevate a skin flap from the underlying parotid fascia, which has a silvery sheen. Carry the flap as anteriorly as necessary to completely resect the lesion. It is important to realize that the branches of the facial nerve approach the flap as elevation proceeds anteriorly and care must be taken not to disrupt the peripheral branches of the facial nerve during flap elevation.
Next, identify the main trunk of the facial nerve. Successful and rapid identification is achieved by using known anatomic landmarks and wide exposure. The important landmarks are the sternocleidomastoid muscle, the cartilaginous external auditory canal and tragal cartilage, the posterior belly of the digastric, the tympanomastoid suture line and associated stylomastoid foramen, and the styloid process. These landmarks are identified sequentially and aid in locating and identifying the main trunk of the facial nerve.
Dissect the tail of the parotid gland anteriorly off the sternocleidomastoid muscle. Take care to preserve the greater auricular nerve if possible. Dissect the tail medially until the posterior belly of the digastric muscle is identified. The posterior belly of the digastric muscle is an important landmark for identifying the facial nerve because the nerve can be identified just superior to the muscle at approximately the same depth.
Next, perform dissection along the anterior aspect of the tragus along the perichondrium. Maintain a wide plane and medially retract the parotid gland . The cartilage forms a point medially, termed the tragal pointer. The facial nerve lies approximately 1 cm deep to this landmark, slightly anterior and inferior. A more reliable landmark is palpation of the tympanomastoid suture line in this region, which separates the mastoid tip from the tympanic portion of the temporal bone. The main trunk of the facial nerve lies at approximately this level or slightly medial. The styloid process may be palpated, and the facial nerve lies between the styloid process and the posterior belly of the digastric muscle as it inserts on the mastoid tip.
The bridge of tissue created between the preauricular dissection and the dissection to the digastric muscle is divided superficially, and then blunt separation of soft tissues is performed in the direction of the facial nerve to identify the main trunk. A nerve stimulator may be helpful in locating the main trunk and branches, but use it sparingly.
In tissue beds previously operated on or in situations in which bulk tumor causes obstruction, this classic method of identifying the facial nerve may be impractical. In these situations, a peripheral branch of the facial nerve may be identified and traced posteriorly to the main trunk. Alternatively, the mastoid tip may be removed with a drill and the facial nerve identified intratemporally as it exits the stylomastoid foramen.
Once the main trunk of the facial nerve is located, use a fine-tipped hemostat to create a tunnel along the nerve and divide the parotid tissue superficially. This method of dissection involves 4 steps using the dissecting hemostat: push, lift, spread, and cut. If the facial nerve is constantly maintained in view, this method eliminates inadvertent injury.
Identify the pes anserinus (the point of main division of the facial nerve) and dissect each branch of the facial nerve out to the periphery. Depending on tumor location, the surgeon may start with either the inferior or the superior division. Once one division is dissected, a tunnel over the next division is superiorly or inferiorly created and connected to the previous dissection. This is repeated for each branch of the facial nerve, reflecting the parotid gland and tumor away from the facial nerve then dissecting the final soft tissue attachments after each branch of the nerve has been identified. Low-level stimulation of the facial nerve at the conclusion of the operation is performed to confirm that all branches are intact.
Other less commonly used methods of identifying the facial nerve include drilling the mastoid bone to identify the facial nerve in its descending segment, as well as finding a distal branch of the facial nerve and performing retrograde dissection.
This technique yields an intact superficial portion of the parotid gland that contains the tumor. Careful hemostasis is achieved with bipolar cautery. Do not use monopolar cautery near the facial nerve. Insert a closed suction drain through a separate stab incision in the hairline and close the wound in layers. Antibiotic ointment and a gauze dressing may be applied.
Limited parotidectomy, also called extracapsular dissection, has recently been espoused as a method to surgically manage benign tumors of the parotid gland. The impetus for this approach came from a study that demonstrated that, in superficial parotidectomy specimens, no margin of normal parenchyma on the deep aspect existed, as the margin was the facial nerve. This information negated the notion that a cuff of normal tissue was needed to prevent recurrence of benign lesions.
A few studies have demonstrated that even with greater than 10-year follow-up, recurrence rates between limited and superficial parotidectomy for pleomorphic adenomas are the same. The advantages of limited parotidectomy are improved cosmesis and decreased rate of Frey syndrome. A potential disadvantage is the seemingly increased risk of unintentional damage to the facial nerve. However, studies have not shown any increased risk of facial nerve injury with limited parotidectomy.
In this technique, the incision and flap elevation are the same as for superficial parotidectomy; however, instead of identifying the main trunk of the facial nerve, the parotid is incised over the tumor. The tumor capsule is then dissected taking care to have adequate visualization and to use a nerve stimulator as needed to avoid injury to branches of the facial nerve. Being as certain as possible that the neoplasm is benign before using limited parotidectomy is important. Preoperative imaging, physical examination, history, and FNA should be consistent with a benign process.
Strictly speaking, total parotidectomy is a misnomer. The procedure, by definition, involves removal of as much parotid tissue medial and lateral to the facial nerve as possible, along with the accompanying tumor. The exact approach varies depending on tumor location, but it usually involves a superficial parotidectomy to identify and preserve the facial nerve, followed by removal of parotid tissue and tumor deep to the facial nerve.
Attempt to preserve the facial nerve at all times. The nerve is never sacrificed for benign disease and only sacrificed if malignancy is found to be directly infiltrating the nerve. In these situations, remove the involved branch with the specimen and obtain frozen sections to ensure clearance of tumor.
Removal of dumbbell-shaped tumors and parapharyngeal space tumors requires additional exposure. This may be accomplished either transcervically after removal of the submandibular gland or via an extended approach with mandibulotomy and/or lip-splitting incision. This is discussed in the Medscape Reference article Parapharyngeal Space Tumors.
For cases of recurrent tumor and in cases in which difficult dissection is anticipated, intraoperative facial nerve monitoring may be helpful in identifying and preserving the facial nerve.
Submandibular gland excision
Submandibular excision is generally performed with the patient under general anesthesia without paralysis. Make a 5-cm incision in a skin crease of the neck approximately 2-3 cm below the inferior border of the mandible. Carry the incision through the platysma and create small subplatysmal flaps inferiorly and superiorly. The surgeon must avoid injuring the marginal mandibular branch of the facial nerve. The procedure may be accomplished by direct identification and dissection superiorly or by incision of the fascia overlying the gland and ligation of the posterior facial vein. The vein and fascia are reflected superiorly, protecting the marginal mandibular nerve.
In managing bulky tumors or malignancy, positive identification and dissection of the marginal mandibular branch not only provides wider exposure but also allows complete excision of the level 1 perifacial lymph nodes with the surgical specimen.
The gland and surrounding tissues are then freed from the undersurface of the mandible. The facial artery is usually divided as it approaches the mandible. Dissect the inferior portion of the gland from the digastric muscle. The facial artery is encountered again inferiorly near its origin from the external carotid artery and ligated. Retract the specimen laterally to expose the mylohyoid muscle. The mylohyoid muscle is dissected free and retracted medially. This maneuver exposes the hypoglossal nerve inferiorly, the lingual nerve superiorly, and the submandibular duct (Wharton duct). Retract the specimen inferiorly and identify the submandibular ganglion along the lingual nerve. The hypoglossal nerve is identified inferiorly. Once the lingual nerve, hypoglossal nerve, and submandibular duct are positively confirmed, ligate and transect the submandibular duct and ganglion. Final soft tissue attachments are divided, and the specimen is removed.
If a neck dissection is indicated, this dissection is performed in continuity. Again, nerves are preserved unless directly involved with tumor. With neurotrophic tumors (adenoid cystic carcinoma), frozen sections may be taken from the epineurium with excision of involved nerves.
Achieve careful hemostasis, insert a closed suction drain or Penrose drain, and close the wound in layers. Antibiotic ointment and a gauze dressing may be applied.
Examination of the facial nerve should be performed in the recovery room as soon as possible. If any uncertainty exists regarding the surgical integrity of the nerve and paralysis of 1 or more branches is discovered, a repeat exploration with cable grafting of injured segments should be performed.
Patients are usually admitted for one night. Closed drains are placed to bulb or wall suction and removed once output diminishes to approximately 30 mL per day (usually on postoperative day 1).
Patients should be monitored for the development of hematomas in the wound, which should be drained if they are discovered.
Facial nerve injury
This is an immediate postoperative complication that can be partial or complete. The surgeon must be confident at termination of the procedure that no branch has been inadvertently divided. If any doubt exists, a repeat exploration is indicated to explore the nerve and repair divided branches. If the nerve is intact, monitor the patient for recovery. The use of steroids in this circumstance is controversial but may have some marginal benefit. This may be because tumor contact or close proximity to the nerve and local inflammatory conditions have been found to be associated with nerve dysfunction after surgery.
Use of ovarian steroids has been effective in rat models in decreasing the amount of apoptosis from trophic insufficiency in peripheral nerves after axotomy. This has led to the use of biodegradable chitosan (ie, chitin-related polymer) prostheses laden with progesterone to bridge gaps in facial nerves after axotomies in rabbits. Preliminary reports have shown increased myelinated fibers in both sides of the incision compared to prostheses with progesterone.
For incomplete eye closure, initiate an eye care program that consists of the use of lubricating drops and ointment to prevent exposure keratopathy. Taping the eyelid closed at night may be useful. Consultation with an ophthalmologist is helpful for monitoring the eye, and reanimation procedures are considered at a later date. If facial nerve resection is required, simultaneous insertion of a gold weight into the upper eyelid may be helpful to prevent postoperative exposure keratopathy.
Careful hemostasis prevents this complication, but repeat exploration is occasionally required in cases that involve hematoma formation.
Sialocele or salivary fistula
This is a relatively common complication following parotid surgery. It may be treated with aspiration and compressive dressings. Fluid should be sent for amylase testing to confirm the diagnosis of sialocele. Anticholinergic medications, such as glycopyrrolate, may be helpful to reduce salivary flow, and botulinum toxin type A has had preliminary success in resolving sialoceles without causing complications such as facial nerve weakness.
Currently, botulinum toxin type A is being investigated as a treatment option for sialoceles. Preliminary results following a single administration of the toxin into the residual parotid gland have yielded a complete resolution of the fistula. Complications such as facial nerve weakness have not been reported.
Frey syndrome or gustatory sweating
This is the most common long-term complication of parotid surgery. It occurs as a result of inappropriate autonomic reinnervation of sweat glands in the skin from parotid parasympathetics. The patient experiences facial sweating and flushing with meals. This complication is not commonly problematic. For significant symptoms, treatment with glycopyrrolate or topical scopolamine may be considered. Various measures to prevent this complication have been suggested, including dermal grafting, fat grafting, AlloDerm placement, subsuperficial musculoaponeurotic system (SMAS) dissection including temporoparietal fascia flaps, maintenance of a thick skin flap, and sternocleidomastoid flaps. Recently, botulinum toxin type A has been used successfully to treat Frey syndrome, and in patients who become immunoresistant to type A, botulinum toxin type F may have an effect.
Sensorineural hearing loss
This has been recently recognized as a possible long-term complication of radiotherapy for neoplasms in the parotid gland. Studies on the effects of ear radiation found that patients with ear structures included in the irradiated field had a 30-40% chance of a 10 dB hearing loss in that ear at 4 kHz or above. A follow-up study revealed that patients who received higher doses of radiation had an increased chance of hearing loss (up to 15 dB at 4 and 8 kHZ) and recommended avoiding a mean dose of greater than 50 Gy to the cochlea.
Outcome and Prognosis
Understanding the factors that influence survival allows surgeons to develop a rational and well–thought-out treatment plan.
Staging of malignant salivary gland tumors is important for predicting prognosis and for accurate comparison of treatment results. The American Joint Committee for Cancer Staging and End Result Reporting (AJCC) has published a tumor, node, and metastases (TNM)–based staging system for major salivary gland malignancies. The 2002 version is summarized in the image below.
This staging system has been developed on the basis of retrospective review of published literature. The system includes tumor size, local extension of tumor, cervical lymph node metastases, and distant metastases. This method of staging has been shown to be correlated with survival. The 5-year relative survival rate is 85% for stage I tumors, 66% for stage II tumors, 53% for stage III tumors, and 32% for stage IV tumors.
A study by Kim et al of 126 patients treated for primary parotid cancer found the following disease-specific survival rates for the various tumor stages (mean follow-up period 29.7 months) :
Stage I (97%)
Stage II (81%)
Stage III (56%)
Stage IV (15%)
Patients in the study underwent superficial, total, or radical parotidectomy, with 57 also undergoing postoperative radiotherapy. Fifteen patients (12%) experienced disease recurrence.
The correlation of the histologic diagnosis with the biologic behavior is not surprising. For this reason, dividing tumors into low-grade and high-grade categories is useful. Low-grade tumors include acinic cell carcinoma and low-grade mucoepidermoid carcinoma. High-grade tumors include adenoid cystic carcinoma, high-grade mucoepidermoid carcinoma, carcinoma ex-pleomorphic adenoma, squamous cell carcinoma, and adenocarcinoma. Low-grade tumors have 10-year survival rates of 80-95%, while 10-year survival rates for high-grade tumors range from 25-50%.
Histopathologic diagnosis is often unavailable at the time of initial surgery, and grading usually cannot be performed with frozen-section analysis. However, frozen sections that can be done has been found have an accuracy of 92.3%, sensitivity of 62.5%, and specificity of 100%. Thus, histologic information is typically not available before surgery. However, histopathologic diagnosis and grade should be considered because they may affect the decision regarding further surgery, elective neck dissection, or adjuvant radiation therapy.
Several new studies that investigated the cellular mechanisms and changes in different salivary gland carcinomas have led to prognostic factors being found at the subcellular level. Ki-67, a nuclear antigen that measures proliferative capacity of a cancer, has been previously used to determine the aggressiveness of other malignancies. When studied in salivary gland cancer samples and correlated with 5 years of patient follow-up, high levels of Ki-67 found in the tumors were strongly correlated with poor survival. Other markers of cell-proliferationlike proteins found in the DNA synthesis phase (S-phase) of mitosis, SKP2, and cyclin A were correlated with a high Ki-67 index and with poor progression-free survival in mucoepidermoid carcinoma.
Looking at proteins associated with local and distant spread also revealed potential markers for prognosis. Immunostaining of malignant salivary gland tumors, including mucoepidermoid, adenocarcinoma, squamous cell, and acinic cell carcinoma, found that the expression of heparinase, an endo-beta-D-glucuronidase, was negatively correlated with survival.
In mucoepidermoid carcinoma, immunostaining for mucin expression can reveal some prognostic information. Cancers with increased MUC1 expression showed increased tumor progression and worse prognosis, but increased MUC4 expression demonstrated decreased progression and better survival.
Lymph node metastases
The occurrence of regional lymph node metastases is related to tumor histopathology and size. The highest rates of lymph node metastases occur with high-grade mucoepidermoid carcinoma (44% of cases), squamous cell carcinoma (36% of cases), adenocarcinoma (26% of cases), undifferentiated carcinoma (23% of cases), and carcinoma ex-pleomorphic adenoma (21% of cases). High-grade mucoepidermoid carcinoma and squamous cell carcinoma have high rates of occult lymph node metastases (16% and 40%, respectively).
Neck dissection is currently performed for any clinically positive disease of the neck (ie, a neck mass), but elective dissection is controversial and not historically done; however, recent studies have shown that the disease recurrence rates were higher in patients without elective neck dissection and that the disease-free survival rate was significantly lower in patients without elective neck dissection. Sentinel lymph node biopsies should be taken from first-echelon lymph nodes, which are exposed during parotidectomy, if they appear suspicious, with further treatment based on pathology. Lymphoscintigraphy can be used intraoperatively to identify sentinel lymph nodes. Neck dissection for the N0 neck may be appropriate in patients with a high probability of occult cervical metastases (eg, those with high-grade mucoepidermoid carcinoma, squamous cell carcinoma, or tumors >4 cm) and with an increased risk of lymphatic spread.
The significance of pain as a presenting symptom with salivary gland masses is not clear because both malignant and benign disease may cause pain. However, among patients who are known to have a malignancy, those who report pain have a lower 5-year survival rate (35% vs 68% for those without pain). Thus, although pain is not a criterion of malignancy, it has poor prognostic significance for patients with malignancy and likely represents invasion of a nerve by tumor.
Facial nerve paralysis
Parotid masses associated with facial paralysis are nearly universally malignant, and this finding portends a poor prognosis. In a review of 1029 cases of parotid malignancy, Eneroth and Hamberger found that 14% of these cases are associated with facial nerve paralysis. Their patients had a 5-year survival rate of 9%.
In 2004, Terhaard et al studied 324 patients with parotid carcinomas and found facial nerve dysfunction to be an independent risk factor for disease-free survival. Those with normal function had a 69% chance compared with 37% with partially dysfunctional facial nerves and 13% with completely impaired function.
Distant metastases clearly portend a poor prognosis. Terhaard et al found an independent correlation between distant metastasis and T and N stage, male sex, perineural invasion, histological type, and skin involvement. Parotid tumors result in distant metastasis in 21% of cases. The rate of distant metastases among high-grade tumors is 32%. For adenoid cystic carcinoma, the distant metastasis rate is nearly 50%. The most common sites are lung and bone. Although patients with metastases from adenoid cystic carcinoma may survive longer than 10 years because of the slow growth of these tumors, their survival with metastatic disease is short. The Dutch group observed the survival rate for patients with adenoid cystic carcinoma with distant metastases is 68% ± 7% in the first year and 32% ± 7% by 5 years. For patients with acinic cell carcinoma, the survival rate with distant metastases is 80% ± 13% at 1 year and 30% ± 14% at 5 years.
Future and Controversies
The optimal management of the facial nerve in parotid malignancies invading a functional nerve is unclear. In instances that the facial nerve is clearly uninvolved, the nerve should be preserved and in cases where the facial nerve is nonfunctional and invaded by tumor, most authors support resection of the nerve. When the nerve is resected, it should be reconstructed with a cable graft, using a cervical sensory nerve or the sural nerve. Margin status of the facial nerve does not appear to affect the functional outcome of cable grafting.
The data are unclear in the instances in which a facial nerve is grossly or microscopically invaded by tumor yet remains functional. In one study, 5-year survival for neoplasms treated with resection with facial nerve preservation was 52%, while tumors treated with radial resection with facial nerve sacrifice was 43%.
Another study found 10-year survival of 74% for nerve preservation and 45% for nerve resection. Selection bias of worse disease being treated with nerve sacrifice in these retrospective studies however, these data suggest that nerve resection does not offer significant, if any, survival benefit. Other studies have demonstrated a trend toward survival benefit for nerve resection to achieve clear surgical margins. In a study of 183 patients with adenoid cystic carcinoma, 10-year survival was 46.8% for nerve preservation and 58.8% for nerve sacrifice. Also, local control at 10 years was 70% for nerve preservation and 100% for nerve sacrifice. Another study found 15-year survival of 37% for nerve preservation and 60% for nerve sacrifice in patients with adenoid cystic carcinoma. So the data is conflicting on whether resection of the facial nerve improves survival. The significant morbidity of a facial nerve palsy must be carefully weighed against any possible oncologic benefit.
Stenner M, Klussmann JP. Current update on established and novel biomarkers in salivary gland carcinoma pathology and the molecular pathways involved. Eur Arch Otorhinolaryngol. 2009 Mar. 266(3):333-41. [Medline].
Straif K, Weiland SK, Bungers M, Holthenrich D, Keil U. Exposure to nitrosamines and mortality from salivary gland cancer among rubber workers. Epidemiology. 1999 Nov. 10(6):786-7. [Medline].
Zheng W, Shu XO, Ji BT, Gao YT. Diet and other risk factors for cancer of the salivary glands:a population-based case-control study. Int J Cancer. 1996 Jul 17. 67(2):194-8. [Medline].
Elledge R. Current concepts in research related to oncogenes implicated in salivary gland tumourigenesis: a review of the literature. Oral Dis. 2009 May. 15(4):249-54. [Medline].
Cheuk W, Chan JK. Advances in salivary gland pathology. Histopathology. 2007 Jul. 51(1):1-20. [Medline].
Mamlouk MD, Rosbe KW, Glastonbury CM. Paediatric parotid neoplasms: a 10 year retrospective imaging and pathology review of these rare tumours. Clin Radiol. 2015 Mar. 70(3):270-7. [Medline].
Yuan WH, Hsu HC, Chou YH, Hsueh HC, Tseng TK, Tiu CM. Gray-scale and color Doppler ultrasonographic features of pleomorphic adenoma and Warthin's tumor in major salivary glands. Clin Imaging. 2009 Sep-Oct. 33(5):348-53. [Medline].
Rong X, Zhu Q, Ji H, et al. Differentiation of pleomorphic adenoma and Warthin's tumor of the parotid gland: ultrasonographic features. Acta Radiol. 2014 Dec. 55(10):1203-9. [Medline].
Adeyemi BF, Kolude BM, Akang EE, Lawoyin JO. A study of the utility of silver nucleolar organizer regions in categorization and prognosis of salivary gland tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Oct. 102(4):513-20. [Medline].
Skalova A, Sima R, Kaspirkova-Nemcova J, et al. Cribriform Adenocarcinoma of Minor Salivary Gland Origin Principally Affecting the Tongue: Characterization of New Entity. Am J Surg Pathol. 2011 Aug. 35(8):1168-1176. [Medline].
Jaehne M, Roeser K, Jaekel T, Schepers JD, Albert N, Loning T. Clinical and immunohistologic typing of salivary duct carcinoma: a report of 50 cases. Cancer. 2005 Jun 15. 103(12):2526-33. [Medline].
Johnson JT, Ferlito A, Fagan JJ, Bradley PJ, Rinaldo A. Role of limited parotidectomy in management of pleomorphic adenoma. J Laryngol Otol. 2007 Dec. 121(12):1126-8. [Medline].
Kim WS, Lee HS, Park YM, et al. Surgical Outcomes of Parotid Cancer: A 10-Year Experience. Otolaryngol Head Neck Surg. 2012 Aug. 147(2 suppl):P180-P181. [Medline].
Eneroth CM, Hamberger CA. Principles of treatment of different types of parotid tumors. Laryngoscope. 1974 Oct. 84(10):1732-40. [Medline].
Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck. 2004 Aug. 26(8):681-92; discussion 692-3. [Medline].
Wax MK, Kaylie DM. Does a positive neural margin affect outcome in facial nerve grafting?. Head Neck. 2007 Jun. 29(6):546-9. [Medline].
Magnano M, gervasio CF, Cravero L, et al. Treatment of malignant neoplasms of the parotid gland. Otolaryngol Head Neck Surg. 1999 Nov. 121(5):627-32. [Medline].
Iseli TA, Karnell LH, Preston TW, et al. Facial nerve sacrifice and radiotherapy in parotid adenoid cystic carcinoma. Laryngoscope. 2008 Oct. 118(10):1781-6. [Medline].
Casler JD, Conley JJ. Surgical management of adenoid cystic carcinoma in the parotid gland. Otolaryngol Head Neck Surg. 1992 Apr. 106(4):332-8. [Medline].
Airoldi M, Pedani F, Succo G, et al. Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer. 2001 Feb 1. 91(3):541-7. [Medline].
Alves FA, Pires FR, De Almeida OP, Lopes MA, Kowalski LP. PCNA, Ki-67 and p53 expressions in submandibular salivary gland tumours. Int J Oral Maxillofac Surg. 2004 Sep. 33(6):593-7. [Medline].
Arabi Mianroodi AA, Sigston EA, Vallance NA. Frozen section for parotid surgery: should it become routine?. ANZ J Surg. 2006 Aug. 76(8):736-9. [Medline].
Aversa S, Ondolo C, Bollito E, Fadda G, Conticello S. Preoperative cytology in the management of parotid neoplasms. Am J Otolaryngol. 2006 Mar-Apr. 27(2):96-100. [Medline].
Bahar G, Dudkiewicz M, Feinmesser R, et al. Acute parotitis as a complication of fine-needle aspiration in Warthin's tumor. A unique finding of a 3-year experience with parotid tumor aspiration. Otolaryngol Head Neck Surg. 2006 Apr. 134(4):646-9. [Medline].
Bajaj Y, Singh S, Cozens N, Sharp J. Critical clinical appraisal of the role of ultrasound guided fine needle aspiration cytology in the management of parotid tumours. J Laryngol Otol. 2005 Apr. 119(4):289-92. [Medline].
Balakrishnan K, Castling B, McMahon J, et al. Fine needle aspiration cytology in the management of a parotid mass: a two centre retrospective study. Surgeon. 2005 Apr. 3(2):67-72. [Medline].
Balakrishnan K, Castling B, McMahon J, et al. Fine needle aspiration cytology in the management of a parotid mass: a two centre retrospective study. Surgeon. 2005 Apr. 3(2):67-72. [Medline].
Batsakis JG, Chinn E, Regezi JA, Repola DA. The pathology of head and neck tumors: salivary glands, part 2. Head Neck Surg. 1978 Nov-Dec. 1(2):167-80. [Medline].
Batsakis JG, Regezi JA. The pathology of head and neck tumors: salivary glands, part 1. Head Neck Surg. 1978 Sep-Oct. 1(1):59-68. [Medline].
Batsakis JG, Regezi JA. The pathology of head and neck tumors: salivary glands, part 4. Head Neck Surg. 1979 Mar-Apr. 1(4):340-9. [Medline].
Bell RB, Dierks EJ, Homer L, Potter BE. Management and outcome of patients with malignant salivary gland tumors. J Oral Maxillofac Surg. 2005 Jul. 63(7):917-28. [Medline].
Bialek EJ, Jakubowski W, Karpinska G. Role of ultrasonography in diagnosis and differentiation of pleomorphic adenomas: work in progress. Arch Otolaryngol Head Neck Surg. 2003 Sep. 129(9):929-33. [Medline].
Boahene DK, Olsen KD, Lewis JE, Pinheiro AD, Pankratz VS, Bagniewski SM. Mucoepidermoid carcinoma of the parotid gland: the Mayo clinic experience. Arch Otolaryngol Head Neck Surg. 2004 Jul. 130(7):849-56. [Medline].
Brackrock S, Krull A, Roser K, Schwarz R, Riethdorf L, Alberti W. Neutron therapy, prognostic factors and dedifferentiation of adenoid cystic carcinomas (ACC) of salivary glands. Anticancer Res. 2005 Mar-Apr. 25(2B):1321-6. [Medline].
Brennan PA, Umar T, Smith GI, McCauley P, Peters WJ, Langdon JD. Expression of type 2 nitric oxide synthase and p53 in Warthin's tumour of the parotid. J Oral Pathol Med. 2002 Sep. 31(8):458-62. [Medline].
Bullerdiek J, Wobst G, Meyer-Bolte K, et al. Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas: correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet Cytogenet. 1993 Jan. 65(1):27-31. [Medline].
Califano J, Eisele DW. Benign salivary gland neoplasms. Otolaryngol Clin North Am. 1999 Oct. 32(5):861-73. [Medline].
Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999 Jul 15. 86(2):207-19. [Medline].
Cesteleyn L, Helman J, King S, Van de Vyvere G. Temporoparietal fascia flaps and superficial musculoaponeurotic system plication in parotid surgery reduces Frey's syndrome. J Oral Maxillofac Surg. 2002 Nov. 60(11):1284-97; discussion 1297-8. [Medline].
Chavez-Delgado ME, Gomez-Pinedo U, Feria-Velasco A, et al. Ultrastructural analysis of guided nerve regeneration using progesterone- and pregnenolone-loaded chitosan prostheses. J Biomed Mater Res B Appl Biomater. 2005 Jul. 74(1):589-600. [Medline].
Chavez-Delgado ME, Mora-Galindo J, Gomez-Pinedo U, et al. Facial nerve regeneration through progesterone-loaded chitosan prosthesis. A preliminary report. J Biomed Mater Res B Appl Biomater. 2003 Nov 15. 67(2):702-11. [Medline].
Chen AM, Garcia J, Bucci MK, Quivey JM, Eisele DW. The role of postoperative radiation therapy in carcinoma ex pleomorphic adenoma of the parotid gland. Int J Radiat Oncol Biol Phys. 2007 Jan 1. 67(1):138-43. [Medline].
Cohen EG, Patel SG, Lin O, et al. Fine-needle aspiration biopsy of salivary gland lesions in a selected patient population. Arch Otolaryngol Head Neck Surg. 2004 Jun. 130(6):773-8. [Medline].
Daa T, Kashima K, Kaku N, Suzuki M, Yokoyama S. Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma. Mod Pathol. 2004 Dec. 17(12):1475-82. [Medline].
Daphna-Iken D, Shankar DB, Lawshe A, Ornitz DM, Shackleford GM, MacArthur CA. MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia. Oncogene. 1998 Nov 26. 17(21):2711-7. [Medline].
Douglas JG, Einck J, Austin-Seymour M, Koh WJ, Laramore GE. Neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands. Head Neck. 2001 Dec. 23(12):1037-42. [Medline].
Douglas JG, Koh WJ, Austin-Seymour M, Laramore GE. Treatment of salivary gland neoplasms with fast neutron radiotherapy. Arch Otolaryngol Head Neck Surg. 2003 Sep. 129(9):944-8. [Medline].
Douglas JG, Silbergeld DL, Laramore GE. Gamma knife stereotactic radiosurgical boost for patients treated primarily with neutron radiotherapy for salivary gland neoplasms. Stereotact Funct Neurosurg. 2004. 82(2-3):84-9. [Medline].
Driemel O, Maier H, Kraft K, Haase S, Hemmer J. Flow cytometric DNA ploidy in salivary gland tumours. Oncol Rep. 2005 Jan. 13(1):161-5. [Medline].
Ellis GL, Auclair PL. Tumors of the Salivary Glands. Center for Medical Education Technologies. Rockville, MD; 1996.
Enamorado I, Lakhani R, Korkmaz H, et al. Correlation of histopathological variants, cellular DNA content, and clinical outcome in adenoid cystic carcinoma of the salivary glands. Otolaryngol Head Neck Surg. 2004 Nov. 131(5):646-50. [Medline].
Enlund F, Nordkvist A, Sahlin P, Mark J, Stenman G. Expression of PLAG1 and HMGIC proteins and fusion transcripts in radiation-associated pleomorphic adenomas. Int J Oncol. 2002 Apr. 20(4):713-6. [Medline].
Foschini MP, Gaiba A, Cocchi R, Pennesi MG, Pession A. p63 expression in salivary gland tumors: role of DeltaNp73L in neoplastic transformation. Int J Surg Pathol. 2005 Oct. 13(4):329-35. [Medline].
Gaillard C, Perie S, Susini B, St Guily JL. Facial nerve dysfunction after parotidectomy: the role of local factors. Laryngoscope. 2005 Feb. 115(2):287-91. [Medline].
Gallipoli A, Manganella G, De Lutiodi di et al. Ultrasound contrast media in the study of salivary gland tumors. Anticancer Res. 2005 May-Jun. 25(3c):2477-82. [Medline].
Gedlicka C, Schüll B, Formanek M, et al. Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies. Anticancer Drugs. 2002 Jun. 13(5):491-5. [Medline].
Genelhu MC, Gobbi H, Soares FA, Campos AH, Ribeiro CA, Cassali GD. Immunohistochemical expression of p63 in pleomorphic adenomas and carcinomas ex-pleomorphic adenomas of salivary glands. Oral Oncol. 2006 Feb. 42(2):154-60. [Medline].
Gilbert J, Li Y, Pinto HA, et al. Phase II trial of taxol in salivary gland malignancies (E1394): a trial of the Eastern Cooperative Oncology Group. Head Neck. 2006 Mar. 28(3):197-204. [Medline].
Govindaraj S, Cohen M, Genden EM, Costantino PD, Urken ML. The use of acellular dermis in the prevention of Frey's syndrome. Laryngoscope. 2001 Nov. 111(11 Pt 1):1993-8. [Medline].
Handra-Luca A, Ruhin B, Lesty C, Fouret P. P27, SKP2, and extra-cellular signal-related kinase signalling in human salivary gland mucoepidermoid carcinoma. Oral Oncol. 2006 Nov. 42(10):1005-10. [Medline].
Harada K, Kawaguchi S, Supriatno, Onoue T, Yoshida H, Sato M. Enhancement of apoptosis in salivary gland cancer cells by the combination of oral fluoropyrimidine anticancer agent (S-1) and radiation. Int J Oncol. 2004 Oct. 25(4):905-11. [Medline].
Heller KS, Attie JN, Dubner S. Accuracy of frozen section in the evaluation of salivary tumors. Am J Surg. 1993 Oct. 166(4):424-7. [Medline].
Heller KS, Attie JN, Dubner S. Accuracy of frozen section in the evaluation of salivary tumors. Am J Surg. 1993 Oct. 166(4):424-7. [Medline].
Huber PE, Debus J, Latz D, et al. Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam?. Radiother Oncol. 2001 May. 59(2):161-7. [Medline].
Johns ME. The salivary glands: anatomy and embryology. Otolaryngol Clin North Am. 1977 Jun. 10(2):261-71. [Medline].
Johns ME, Goldsmith MM. Current management of salivary gland tumors. Part 2. Oncology (Williston Park). 1989 Mar. 3(3):85-91; discussion 94, 99. [Medline].
Johns ME, Goldsmith MM. Incidence, diagnosis, and classification of salivary gland tumors. Part 1. Oncology (Williston Park). 1989 Feb. 3(2):47-56; discussion 56, 58, 62. [Medline].
Johns MM 3rd, Westra WH, Califano JA, Eisele D, Koch WM, Sidransky D. Allelotype of salivary gland tumors. Cancer Res. 1996 Mar 1. 56(5):1151-4. [Medline].
Kerawala CJ, McAloney N, Stassen LF. Prospective randomised trial of the benefits of a sternocleidomastoid flap after superficial parotidectomy. Br J Oral Maxillofac Surg. 2002 Dec. 40(6):468-72. [Medline].
Koyuncu M, Sesen T, Akan H, et al. Comparison of computed tomography and magnetic resonance imaging in the diagnosis of parotid tumors. Otolaryngol Head Neck Surg. 2003 Dec. 129(6):726-32. [Medline].
Kyrmizakis DE, Pangalos A, Papadakis CE, Logothetis J, Maroudias NJ, Helidonis ES. The use of botulinum toxin type A in the treatment of Frey and crocodile tears syndromes. J Oral Maxillofac Surg. 2004 Jul. 62(7):840-4. [Medline].
Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin. 1998 Jan-Feb. 48(1):6-29. [Medline].
Lee JH, Lee JH, Kim A, Kim I, Chae YS. Unique expression of MUC3, MUC5AC and cytokeratins in salivary gland carcinomas. Pathol Int. 2005 Jul. 55(7):386-90. [Medline].
Li J, El-Naggar A, Mao L. Promoter methylation of p16INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma. Cancer. 2005 Aug 15. 104(4):771-6. [Medline].
Lim JJ, Kang S, Lee MR, et al. Expression of vascular endothelial growth factor in salivary gland carcinomas and its relation to p53, Ki-67 and prognosis. J Oral Pathol Med. 2003 Oct. 32(9):552-61. [Medline].
Luukkaa H, Klemi P, Leivo I, Vahlberg T, Grenman R. Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: an evaluation of 212 cases. Acta Oncol. 2006. 45(6):669-75. [Medline].
MacLusky NJ, Chalmers-Redman R, Kay G, Ju W, Nethrapalli IS, Tatton WG. Ovarian steroids reduce apoptosis induced by trophic insufficiency in nerve growth factor-differentiated PC12 cells and axotomized rat facial motoneurons. Neuroscience. 2003. 118(3):741-54. [Medline].
Mantesso A, Loducca SV, Bendit I, Garicochea B, Nunes FD, de Araujo VC. Mdm2 mRNA expression in salivary gland tumour cell lines. J Oral Pathol Med. 2004 Feb. 33(2):96-101. [Medline].
Marchese-Ragona R, Marioni G, Restivo DA, Staffieri A. The role of botulinum toxin in postparotidectomy fistula treatment. A technical note. Am J Otolaryngol. 2006 May-Jun. 27(3):221-4. [Medline].
Maruya S, Namba A, Matsubara A, et al. Salivary gland carcinoma treated with concomitant chemoradiation with intraarterial cisplatin and docetaxel. Int J Clin Oncol. 2006 Oct. 11(5):403-6. [Medline].
Matizonkas-Antonio LF, de Mesquita RA, de Souza SC, Nunes FD. TP53 mutations in salivary gland neoplasms. Braz Dent J. 2005. 16(2):162-6. [Medline].
Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Villaret DB. Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer. 2005 Jun 15. 103(12):2544-50. [Medline].
Miyake H, Matsumoto A, Hori Y, et al. Warthin's tumor of parotid gland on Tc-99m pertechnetate scintigraphy with lemon juice stimulation: Tc-99m uptake, size, and pathologic correlation. Eur Radiol. 2001. 11(12):2472-8. [Medline].
Moreira JM, Ohlsson G, Rank FE, Celis JE. Down-regulation of the tumor suppressor protein 14-3-3sigma is a sporadic event in cancer of the breast. Mol Cell Proteomics. 2005 Apr. 4(4):555-69. [Medline].
Motoori K, Yamamoto S, Ueda T, et al. Inter- and intratumoral variability in magnetic resonance imaging of pleomorphic adenoma: an attempt to interpret the variable magnetic resonance findings. J Comput Assist Tomogr. 2004 Mar-Apr. 28(2):233-46. [Medline].
North CA, Lee DJ, Piantadosi S, Zahurak M, Johns ME. Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1990 Jun. 18(6):1319-26. [Medline].
Otsuka H, Graham MM, Kogame M, Nishitani H. The impact of FDG-PET in the management of patients with salivary gland malignancy. Ann Nucl Med. 2005 Dec. 19(8):691-4. [Medline].
Petit T, Bearss DJ, Troyer DA, Munoz RM, Windle JJ. p53-independent response to cisplatin and oxaliplatin in MMTV-ras mouse salivary tumors. Mol Cancer Ther. 2003 Feb. 2(2):165-71. [Medline].
Raimondi AR, Vitale-Cross L, Amornphimoltham P, Gutkind JS, Molinolo A. Rapid development of salivary gland carcinomas upon conditional expression of K-ras driven by the cytokeratin 5 promoter. Am J Pathol. 2006 May. 168(5):1654-65. [Medline].
Raine C, Saliba K, Chippindale AJ, McLean NR. Radiological imaging in primary parotid malignancy. Br J Plast Surg. 2003 Oct. 56(7):637-43. [Medline].
Rau AR, Kini H, Pai RR. Tissue effects of fine needle aspiration on salivary gland tumours. Indian J Pathol Microbiol. 2006 Apr. 49(2):226-8. [Medline].
Raymond MR, Yoo JH, Heathcote JG, McLachlin CM, Lampe HB. Accuracy of fine-needle aspiration biopsy for Warthin's tumours. J Otolaryngol. 2002 Oct. 31(5):263-70. [Medline].
Rohen C, Rogalla P, Meyer-Bolte K, Bartnitzke S, Chilla R, Bullerdiek J. Pleomorphic adenomas of the salivary glands: absence of HMGIY rearrangements. Cancer Genet Cytogenet. 1999 Jun. 111(2):178-81. [Medline].
Roijer E, Nordkvist A, Strom AK, et al. Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma. Am J Pathol. 2002 Feb. 160(2):433-40. [Medline].
Roob G, Fazekas F, Hartung HP. Peripheral facial palsy: etiology, diagnosis and treatment. Eur Neurol. 1999 Jan. 41(1):3-9. [Medline].
Russo G, Zamparelli A, Howard CM, et al. Expression of cell cycle-regulated proteins pRB2/p130, p107, E2F4, p27, and pCNA in salivary gland tumors: prognostic and diagnostic implications. Clin Cancer Res. 2005 May 1. 11(9):3265-73. [Medline].
Sakamoto M, Sasano T, Higano S, Takahashi S, Iikubo M, Kakehata S. Usefulness of heavily T(2) weighted magnetic resonance images for the differential diagnosis of parotid tumours. Dentomaxillofac Radiol. 2003 Sep. 32(5):295-9. [Medline].
Schuller DE, McCabe BF. Salivary gland neoplasms in children. Otolaryngol Clin North Am. 1977 Jun. 10(2):399-412. [Medline].
Shikhani AH, Johns ME. Tumors of the major salivary glands in children. Head Neck Surg. 1988 Mar-Apr. 10(4):257-63. [Medline].
Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996 Jul. 7(5):548-57. [Medline].
Spiro RH. Changing trends in the management of salivary tumors. Semin Surg Oncol. 1995 May-Jun. 11(3):240-5. [Medline].
Spiro RH. Management of malignant tumors of the salivary glands. Oncology (Williston Park). 1998 May. 12(5):671-80; discussion 683. [Medline].
Spiro RH, Huvos AG, Strong EW. Cancer of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg. 1975 Oct. 130(4):452-9. [Medline].
Stannard CE, Hering E, Hough J, Knowles R, Munro R, Hille J. Post-operative treatment of malignant salivary gland tumours of the palate with iodine-125 brachytherapy. Radiother Oncol. 2004 Dec. 73(3):307-11. [Medline].
Stern SJ, Suen JY. Salivary gland tumors. Curr Opin Oncol. 1993 May. 5(3):518-25. [Medline].
Stow N, Veivers D, Poole A. Fine-needle aspiration cytology in the management of salivary gland tumors: an Australian experience. Ear Nose Throat J. 2004 Feb. 83(2):128-31. [Medline].
Stárek I, Koranda P, Zboøil V, Mrzena L. Sentinel lymph node biopsy in parotid gland carcinoma. Clin Nucl Med. 2006 Apr. 31(4):203-4. [Medline].
Suzuki K, Cheng J, Watanabe Y. Hepatocyte growth factor and c-Met (HGF/c-Met) in adenoid cystic carcinoma of the human salivary gland. J Oral Pathol Med. 2003 Feb. 32(2):84-9. [Medline].
Taki S, Yamamoto T, Kawai A, Terahata S, Kinuya K, Tonami H. Sonographically guided core biopsy of the salivary gland masses: safety and efficacy. Clin Imaging. 2005 May-Jun. 29(3):189-94. [Medline].
Tan LG, Khoo ML. Accuracy of fine needle aspiration cytology and frozen section histopathology for lesions of the major salivary glands. Ann Acad Med Singapore. 2006 Apr. 35(4):242-8. [Medline].
Terhaard CH, Lubsen H, Rasch CR, et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys. 2005 Jan 1. 61(1):103-11. [Medline].
Tsang YT, Chang YM, Lu X, Rao PH, Lau CC, Wong KK. Amplification of MGC2177, PLAG1, PSMC6P, and LYN in a malignant mixed tumor of salivary gland detected by cDNA microarray with tyramide signal amplification. Cancer Genet Cytogenet. 2004 Jul 15. 152(2):124-8. [Medline].
Tugnoli V, Marchese Ragona R, Eleopra R, De Grandis D, Montecucco C. Treatment of Frey syndrome with botulinum toxin type F. Arch Otolaryngol Head Neck Surg. 2001 Mar. 127(3):339-40. [Medline].
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2001 Incidence and Mortality. Atlanta (GA): Department of Health and Human Services, Centers for Disease Contr. 2004.
Urquhart A, Hutchins LG, Berg RL. Preoperative computed tomography scans for parotid tumor evaluation. Laryngoscope. 2001 Nov. 111(11 Pt 1):1984-8. [Medline].
van der Putten L, de Bree R, Plukker JT, et al. Permanent unilateral hearing loss after radiotherapy for parotid gland tumors. Head Neck. 2006 Oct. 28(10):902-8. [Medline].
Van Heerden WF, Raubenheimer EJ, Dreyer L. The role of DNA ploidy and Ki-67 in the grading of mucoepidermoid carcinomas. Anticancer Res. 2005 May-Jun. 25(3c):2589-92. [Medline].
Vargas H, Galati LT, Parnes SM. A pilot study evaluating the treatment of postparotidectomy sialoceles with botulinum toxin type A. Arch Otolaryngol Head Neck Surg. 2000 Mar. 126(3):421-4. [Medline].
Voz ML, Astrom AK, Kas K, Mark J, Stenman G, Van de Ven WJ. The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter. Oncogene. 1998 Mar. 16(11):1409-16. [Medline].
Wan YL, Chan SC, Chen YL, et al. Ultrasonography-guided core-needle biopsy of parotid gland masses. AJNR Am J Neuroradiol. 2004 Oct. 25(9):1608-12. [Medline].
Wang L, Sun M, Jiang Y, et al. Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg. 2006 Apr. 64(4):636-41. [Medline].
Waterman M, Ben-Izhak O, Eliakim R, Groisman G, Vlodavsky I, Ilan N. Heparanase upregulation by colonic epithelium in inflammatory bowel disease. Mod Pathol. 2007 Jan. 20(1):8-14. [Medline].
Weber A, Langhanki L, Schutz A, Gerstner A, Bootz F, Wittekind C. Expression profiles of p53, p63, and p73 in benign salivary gland tumors. Virchows Arch. 2002 Nov. 441(5):428-36. [Medline].
Westernoff TH, Jordan RC, Regezi JA, Ramos DM, Schmidt BL. Beta-6 Integrin, tenascin-C, and MMP-1 expression in salivary gland neoplasms. Oral Oncol. 2005 Feb. 41(2):170-4. [Medline].
Yabuuchi H, Fukuya T, Tajima T, Hachitanda Y, Tomita K, Koga M. Salivary gland tumors: diagnostic value of gadolinium-enhanced dynamic MR imaging with histopathologic correlation. Radiology. 2003 Feb. 226(2):345-54. [Medline].
Yamamoto Y, Kishimoto Y, Wistuba II, et al. DNA analysis at p53 locus in carcinomas arising from pleomorphic adenomas of salivary glands: comparison of molecular study and p53 immunostaining. Pathol Int. 1998 Apr. 48(4):265-72. [Medline].
Yih WY, Kratochvil FJ, Stewart JC. Intraoral minor salivary gland neoplasms: review of 213 cases. J Oral Maxillofac Surg. 2005 Jun. 63(6):805-10. [Medline].
Zbaren P, Schar C, Hotz MA, Loosli H. Value of fine-needle aspiration cytology of parotid gland masses. Laryngoscope. 2001 Nov. 111(11 Pt 1):1989-92. [Medline].
Zbaren P, Schupbach J, Nuyens M, Stauffer E. Elective neck dissection versus observation in primary parotid carcinoma. Otolaryngol Head Neck Surg. 2005 Mar. 132(3):387-91. [Medline].
Zhang J, Peng B, Chen X. Expressions of nuclear factor kappaB, inducible nitric oxide synthase, and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands: correlations with the angiogenesis and clinical outcome. Clin Cancer Res. 2005 Oct 15. 11(20):7334-43. [Medline].
Zhao X, Ren W, Yang W, et al. Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice. Int J Cancer. 2006 Feb 1. 118(3):643-8. [Medline].