Salivary Gland Cancer: Teamwork Pays Off

George Monemvasitis; Bhuvanesh Singh, MD

Disclosures

January 23, 2015

Editor's Note:

Salivary gland cancers are rare, morphologically diverse malignancies, representing less than 1% of all cancers in the United States.[1] Although they are an understudied group, salivary gland cancers are associated with 5-year survival rates of greater than 70% across all stages. Because of the accessibility of the majority of the involved anatomical sites, these malignancies are often found during the early stages of cancer development, and in patients with stage I disease, the 5-year survival rate is greater than 90%.[1]

In an interview with Medscape, Bhuvanesh Singh, MD, a surgical oncologist with the Head and Neck Service, Department of Surgery, and the director of the Laboratory of Epithelial Cancer Biology at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, discussed the best predictors of survival, the balance between over- and undertreatment, and other challenges faced in researching and managing a rare cancer.

Medscape: Could you give us a brief description of the types of salivary gland cancer and the most common sites of presentation in relation to the mouth, neck, and throat?

Dr Singh: Salivary gland cancers are broadly classified by site of origin, as either minor or major salivary glands. The major salivary glands are paired structures that include the parotid, submandibular, and sublingual glands.

The parotid gland lies in front, underneath, and behind the ear. The most common presentation is a preauricular mass, or a mass in the cheek beneath the skin, that is usually not attached to the skin. Lymph nodes can also be found in this area, so it's important to make a distinction between the two. Submandibular glands are found just below the jawbone at the paramedian position on either side. The sublingual glands are located just below the surface mucosa of the floor of the mouth.

The minor salivary glands number in the hundreds; they line the oral cavity, the palate, the sinus tract, oropharynx, and the larynx. They basically can be anywhere in the upper aerodigestive tract, with the highest density seen in the palate region.

All of these salivary glands are subject to cancer formation. The parotid gland is by far the most common site for the development of a neoplastic process, benign or malignant. Approximately 25% of growths in the parotid gland, 50% in the submandibular gland, and 75% in the minor salivary glands tend to be cancerous.[2] But the numbers are calculated mostly on the basis of what is seen at referral centers and may actually represent an overestimation of the true incidence of malignancy. Cancers are less common in the sublingual glands.

A wide range of cancers with divergent behaviors can arise within the salivary glands. Mucoepidermoid carcinoma is the most common histologic subtype in the parotid gland. Adenoid cystic carcinomas are the most common type of cancer in minor and submandibular salivary glands. However, any subtype can occur in each of the salivary glands.

Factors That Raise the Suspicion of Malignancy

Medscape: What are the best predictors of survival outcome in patients with salivary gland cancer?

Dr Singh: In general, the two most important predictive factors for prognosis are the stage of the cancer—probably the most important factor—and the grade of the tumor. Advanced-stage cancers do worse than early-stage cancers, as expected. The overall survival rate is greater than 90% for stage I cancer, 70%-75% for stage II cancer, and approximately 20% for stage III and IV cancers.[3]

High-grade cancers tend to be more aggressive, with a higher propensity for local infiltration and spread to both the regional nodes and to distant sites. Low-grade cancers are much less aggressive, and the primary issue with them is local disease. As such, adequate treatment of the primary cancer is usually sufficient for the management of low-grade salivary cancers. The best outcomes are seen with the low-grade, low-stage cancers.

Medscape: Considering that most salivary gland masses are benign, are there any subtle symptoms or indications that would increase suspicion of malignancy, and at what point should a primary care physician, dentist, or community oncologist make a referral to a specialized surgeon?

Dr Singh: Both benign and malignant masses of salivary gland typically present as isolated, painless masses. Unfortunately, most salivary gland cancers do not cause symptoms until they're more advanced. In many cases, it is difficult to distinguish between benign and malignant pathology solely on the basis of clinical evaluation. In general, any persistent mass in a salivary gland or in the region of a salivary gland merits further evaluation.

Not every patient with a parotid or submandibular mass needs to be referred, because many of these masses will be inflamed lymph nodes. If they're tender to palpation or associated with an upper respiratory infection or another predisposing factor, you can suggest a period of observation for the patient. Waiting 6-8 weeks will generally not change the outcome, even if the mass is cancerous; that's usually what's required for an inflamed lymph node to shrink in size. But if the mass persists for more than 8 weeks, and especially if it's growing in size, referral should be considered.

In contrast, masses associated with symptoms, such as facial paralysis, or those that are fixed, firm, or have ill-defined borders should prompt immediate referral to an appropriate specialist.

BRCA Mutations Linked to Salivary Gland Cancer

Medscape: What are some of the factors that increase the risk for salivary gland cancer? Do inherited genetic abnormalities play a role?

Dr Singh: The current prevailing theory is that cancer development reflects an imbalance between mutagenic signals and our body's ability to repair the genetic damage that they cause. In most cases, there are no identifiable mutagenic signals that promote salivary gland cancer formation.

Radiation exposure has been associated with the development of salivary gland cancer. The link with radiation exposure comes from populations exposed to atomic bomb fallout in Hiroshima and Nagasaki. These individuals have a significantly higher risk of developing major salivary gland cancers.[4] Patients undergoing therapeutic radiation that exposes the salivary glands may also have a slightly higher risk.

Other, softer associations include wood dust exposure, specifically wood dust exposure to the sinonasal cavity. Some data suggest that exposure to softwood dust is associated with a higher rate of squamous cell cancer in the nasal cavity,[5] which is a non-salivary gland cancer. Exposure to hardwood dust, mainly in woodworkers, has been associated with adenocarcinoma,[6] which is a salivary gland cancer.

For many diseases, inherited genetic abnormalities can predispose individuals to cancer formation. As an example, abnormalities in oncogenes such as RET, BRCA1, and BRCA2 are heritable and predispose individuals to cancer formation. Recently, a study reported that persons with BRCA mutations have a 20-fold increased risk for salivary gland carcinoma than the general population.[7] This is the first report, to my knowledge, linking salivary gland cancer to a heritable genetic abnormality.

Several somatic, or acquired, genetic changes have been identified. One of the most common is a translocation of chromosome 11 to chromosome 19 [t11:19], which leads to a fusion protein between MECT and MAML2.[8] The fusion protein resulting from this translocation is thought to activate notch signaling, which promotes cancer formation and progression. A wide range in the prevalence of t11:19 has been reported in the literature, with an average of approximately 40% in mucoepidermoid carcinomas. Of note, the presence of this abnormality is actually associated with less aggressive behavior in mucoepidermoid carcinomas.

Our group at MSKCC has worked on adenoid cystic carcinomas.[9] We didn't find a high density of mutations in this disease, and the ones that were present were scattered amongst multiple genes. Genetic changes identified can be grouped into different pathways, including those that affect epigenetic factors, the MYB/Myc signaling pathway, the DNA damage/checkpoint repair signaling pathway, the FGF/IGF/PI3K signaling pathway, and the Notch signaling pathway. The precise clinical significance of these abnormalities has yet to be defined.

Team Effort to Individualize Treatment

Medscape: Could you describe the role of a multidisciplinary team approach to the management of this disease?

Dr Singh: Many salivary gland cancers require multimodality treatment. Most low-grade, early-stage cancers can be managed with surgery alone. On the other hand, multimodality management is required for advanced-stage cancers. Careful pretreatment planning is required to get optimal outcomes, and the presence of a qualified multidisciplinary team is essential in these cases.

The role of the multidisciplinary team is to individualize treatment for patients with salivary gland cancer on the basis of tumor location, histologic subtype, and extent of disease, as well as the patient's overall health status. In general, surgical resection is performed whenever possible for advanced cancers, and adjuvant radiation, and in selected cases chemoradiation, is added to increase the locoregional control rate. In cases of unresectable disease, recent reports suggest that proton-based radiation may offer a chance of disease control.[10] Chemotherapy is typically used in cases that are refractory to other treatment modalities or have metastasized to distant sites.

The role of primary chemotherapy is not well established; there is some anecdotal information that suggests chemotherapy might be beneficial for some types of salivary cancers. In salivary ductal carcinoma, a relatively rare, aggressive cancer that has been shown to express androgen receptor, antiandrogen therapy has shown dramatic responses in many patients.[11] Unfortunately, no established targeted therapies have been developed for salivary cancers to date. However, recent genetic analyses have identified potentially targetable abnormalities in these tumors. Our team is looking at approaches to explore these genetic changes in order to improve the outcomes of patients with salivary gland cancers.

Medscape: What factors do you take into consideration to balance the need for tumor eradication and preserving facial appearance and nerve and muscle integrity?

Dr Singh: The challenge for any cancer treatment is trying to balance the effect of the treatment with its benefit. Clearly, the primary goal is to eradicate the cancer. Achieving an optimal balance should take into account the aggressiveness of the disease and can be quite challenging. This is where comprehensive planning from an experienced team of clinicians makes a significant difference.

When we approach patients with salivary gland cancers, we make all attempts to minimize the cosmetic and functional effects of treatment in all cases. Surgery is a mainstay of treatment for most patients with salivary gland cancers. Surgeries for salivary gland cancers are quite intricate and can lead to cosmetic changes and functional effects, especially in the case of surgery for parotid gland cancers. Even when parotid gland surgery is done successfully, cosmetic changes can occur, especially in the cheek area and the angle of the jaw, which can become more prominent and visible.[12]

Cosmetic Repair: Yes or No?

Dr Singh: There's controversy as to whether you should try to correct the cosmetic changes that result from tumor resection. Some people put in artificial substances or grafts to fill that area in, but it can make future examinations more difficult. If you're worried about the cancer coming back, you may not necessarily want to hide it by putting something in the surgical bed solely to improve aesthetics.

There are other surgical techniques as well. Parotid gland surgery, for example, can be done through a facelift-like incision, after which it is hard to see scars.[13] All of these options need to be discussed and planned preoperatively in order to get the best cosmetic and functional outcomes.

As a general rule, we make all attempts to preserve the facial nerve if it's functioning preoperatively. However, there are situations in which you do need to remove the facial nerve, such as when a high-grade cancer is surrounding or encasing the nerve. Sometimes you can see evidence of perineural extension, where tumor can track along the nerve—that's especially true for adenoid cystic carcinoma; in earlier stages, perineural extension may not affect nerve function. In these cases, however, you have to take the nerve, even if the nerve is functioning preoperatively.

When the facial nerve has to be resected, several approaches can be applied to optimize functional results at the time of surgery, including nerve grafting. In addition, facial reanimation procedures are available postoperatively as well. An experienced team that includes a cancer and reconstructive surgeon are required to achieve the best outcomes in these situations.

Precise Delivery of Radiation

Dr Singh: Similar to surgery, the technique with which radiation is delivered can have significant functional and cosmetic effects. Experienced radiation oncologists, especially ones specializing in head and neck radiation, can often mold radiation portals in a manner that minimizes effects on normal tissues. In addition, different types of radiation allow for better control and therefore decrease exposure of normal tissues to the radiation treatment.

As an example, proton-based radiation can be delivered more precisely to the cancer areas while minimizing exposure to normal tissues, which can significantly decrease risk for long-term, radiation-related side effects. Moreover, there has been some suggestion that advanced adenoid cystic carcinomas, especially when they occur in the sinonasal cavity at the skull base, can be treated effectively with protons without causing surgical or functional compromise to the patient.[10] So there are avenues for improved outcomes and function using radiation-based treatments as well.

Another key to minimizing the effects of treatment is to avoid overtreatment. As an example, for most early-stage, low-grade salivary gland cancers, surgery alone is sufficient for cure. One of the critical issues when managing low-risk cancers is the impact of surgical margins on use of adjuvant treatment.

There are cases of overtreatment of low-grade malignancies in which adjuvant radiation is given solely on the basis of the pathology report discussing an abnormal margin. Because many of these tumors occur very close to the facial nerve, you will often try to preserve the nerve as long as you feel you're getting the entire cancer out. Even with positive margins, many times we don't recommend additional adjuvant treatment, but it requires significant experience to decide who is going benefit from this and who is not.

Medscape: What are some of the challenges oncologists face in managing salivary gland cancer?

Dr Singh: This is a very rare disease, and if you look at the clinical trial options that are available, there aren't many. A lot of the trials are multidisease trials in which salivary gland cancer is mixed in. It's been difficult to conduct trials for salivary gland cancers because of the limited number of patients for enrollment.

The biggest challenge is refractory disease, because we have very few options there. The response to single- and multiple-agent chemotherapy for these patients is not very good.[14] There's a significant need for the development of new treatment options. Because of the rarity of the disease, there is a lack of information about their genetic composition, and there aren't many options that target the genetic abnormalities that develop in these patients. The research we performed that looked at adenoid cystic carcinoma was a pretty significant advance in our understanding of salivary gland cancers.[9]

I think as we move forward, we face two big issues: (1) integrating the work of multiple centers to advance our understanding of these cancers at the genetic level, and (2) initiating clinical trials that could be developed from that genetic information so that we can get sufficient sample sizes to answer efficacy and safety questions. As in many other cancers, cancer biology is probably the biggest issue and the most obvious way to improve treatments, but the rarity of the disease limits our ability to perform meaningful studies.

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