Bobby R. Alford Department of
Otolaryngology-Head and Neck Surgery
Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature.
Management of Malignant Salivary Gland Neoplasms
Shane Pahlavan, M.D.
November 1, 2007
The topic of discussion today is the management of malignant salivary gland neoplasms. We will discuss the case presentation as well as a brief historical review and the epidemiology. We will talk a bit about the clinical history and how these patients present, as well as the classification of the different neoplasms. We will go into some detail of the histologic subtypes. We will talk about the most common subtypes, but will mention all of them. We will also go into a brief discussion of the diagnosis and the management as well as some of the controversies in the management of these lesions.
JP is a 59-year-old male who presented with an enlarging right neck mass that have been present since he was 25 years of age. He described the mass as initially growing slowly, but increasing in the growth rate recently with the addition of intermittent dysphagia to solids. Additionally, he did notice some redness and breakdown of the skin overlying the lesion. He denied any pain, fevers, chills, shortness of breath, hoarseness, otalgia, or unintentional weight loss. Past medical history was unremarkable. He did specifically deny previous low-dose radiation of the head and neck, had no previous surgeries, was not currently on any medications and he had no known drug allergies. He is a social drinker. He does have 25-pack year smoking history, denied any illicit drug use, and is unemployed. Family history is significant for history of coronary artery disease in both his mother and father. On physical examination, generally, he was in no apparent distress. Ears, nose, oral cavity, and oropharynx exam were within normal limits, except for some poor dentition. Subsequent to his neck exam, he did have a firm, poorly mobile, right neck mass measuring 10cm x 12cm. There was some erythema of the overlying skin with some gross tumor invasion. However, there was no associated lymphadenopathy. On flexible laryngoscopy, both bilateral true vocal cords were mobile. No masses or lesions were noted. Neurologically, cranial nerves II through XII are functional bilaterally. In this picture of our patient you can see that the right neck mass extends inferior to the mandible, and you can see the thick lesion of overlying skin that he noticed had become soft and had eroded through the skin itself. He underwent a fine needle aspiration of the right submandibular gland, which did show some atypical cells, which were positive for neoplasia, most consistent with pleomorphic adenoma. A CT neck with contrast was done and showed an 11.2 x 12.5 x 10.6 cm partially necrotic right neck mass, arising from the right submandibular gland without any evidence of lymphadenopathy. He underwent a resection of the mass with right submandibular gland excision.
The first reported salivary gland disease with neoplasm was within the mid 17th century with the anatomy of the parotid gland and the role of the main ducts. It was described by the Greeks, preauricular swelling associated primarily with calculi and inflammation. Over the next 100 years or so, salivary gland surgery was primarily limited to the treatment of ranulas and oral calculi. Surgical excision of a parotid tumor has been attributed to Bertrandi in 1802. The initial applications of this surgery included an extensive approach that caused serious disfigurement and disability. Over the next 100 years, until approximately 1850, the focus shifted toward dissection of the more intermittent relationship between the facial nerve and the parotid gland.
Malignant neoplasms of the salivary gland are relatively rare, accounting for just 6% of all head and neck malignancies. The literature suggests that an estimated 1 in 100,000 US residents will develop a salivary gland malignancy, with the average age being 56.6 years. Benign neoplasms do occur more frequently in women than men, but interestingly, the malignant tumors have equal distribution between both sexes.
This chart documents where salivary gland neoplasms are often found. The most common site of neoplasms of the salivary gland will be seen in the parotid, with 20-30% of these being malignant. In the submandibular gland, about 10-15% of the neoplasms, roughly half, were of a malignant variety. The sublingual and minor salivary glands make up about 5-10% of salivary gland neoplasms. Interestingly, 90% of sublingual glands are malignant and 60% of minor salivary glands are malignant.
Malignant salivary gland neoplasms present as painless masses in approximately 75% of the patients or more, as some literature suggests. Rarely, these patients present to clinic initially with pain or facial nerve palsy. Usually, a palpable mass will be seen arising from one of the salivary glands. If there is associated pain or nerve paralysis, this finding is concerning for a malignant lesion rather than a benign adenoma. It is believed that episodic pain suggests more of a continued obstruction from a calculi, whereas constant pain is more suggestive of malignancy. Upon the initial presentation of the patient, other factors that may suggest malignancy include trismus, cervical adenopathy, fixation to the skin, numbness, loose dentition, or associated bleeding.
This is the most commonly used classification and is from the American Joint Committee on Cancer and is the most reliable predicted outcome of any extensive disease at presentation.
There are multiple histologic subtypes of salivary gland neoplasms and cancers. Specifically, we will talk about the most common histological types including mucoepidermoid carcinoma, adenoid cystic, acinic cell carcinoma, and some of the mixed tumors including carcinoma ex-pleomorphic and carcinosarcoma. Some of the other causes of parotid gland neoplasms include sarcoma and lymphoma and are beyond the scope of this lecture.
First we will start with mucoepidermoid carcinoma. This is the most common malignant tumor in the parotid gland. It can occur in roughly 30-45% of parotid malignancies and is the second most common malignant tumor of the submandibular gland. It is the most common salivary gland malignancy in children, interestingly. It is composed of two populations of cells: mucinous and epidermoid cells. The proportion of cell type defines the grade of the tumor. It is commonly induced by radiation and has a 30-70% overall regional metastatic potential. Low-grade mucoepidermoid carcinomas that are considered well-differentiated have a high ratio of mucinous cells to epidermoid cells. These have a 70% five-year survival rate. This is in contrast to the higher grade carcinomas, which are poorly differentiated, which have an inverse ratio with a higher proportion of epidermoid to mucinous cells. This is obviously a more aggressive tumor, with less than 50% five-year survival. On the right of this slide is a low-grade carcinoma. You can see some cells that centered on the slide that are epidermoid in composition with some mitotic features, but you can see clearly mucinous cells here in the bottom left as well as on the right. So, this was graded as a low-grade carcinoma. There is an intermediate grade of mucoepidermoid carcinoma that some literature suggests may be in between low and high-grade carcinomas. This grade has less mucinous cells than the low-grade and may have more mitotic features, but not yet enough to be classified as the high-grade carcinomas.
Adenoid cystic carcinoma is the most common submandibular and minor gland malignancy and is a highly aggressive tumor with an insidious onset. It does have a predilection for perineural invasion and, consequently, it is difficult to eradicate the tumor completely. Treatment failure is due to local recurrence and distant metastasis can occur, most commonly to the lung. Here is a histologic slide of adenoid cystic carcinoma. There are three histologic types: cribriform, tubular, and solid. The most common and easily recognizable is the cribriform, which some literature calls the “swiss cheese pattern.” This type is arranged in nests around cylindrical spaces containing mucinous or hyalinized material. It is the most benign in behavior and carries the best prognosis. The tubular pattern is characterized by cells that are arranged in layers and form ductal structures. The solid pattern is the most malignant and is highly cellular, containing sheaths of the tumor cell with no intervening spaces.
Acinic cell carcinoma located in the parotid gland in 95% of cases due to the fact that it is composed of serous cells found primarily in the parotid gland. The tumor usually has low-grade behavior and the best survival rate of any of the salivary gland malignancies. It does show bilateral involvement in 3% of the cases, which is actually second to the more benign Warthin’s tumor, which shows bilateral involvement in 10% of cases. Histologic subtypes include cystic, papillary, vacuolated, and follicular.
With respect malignant mixed tumors, the two most commonly discussed in the literature are carcinosarcoma and the carcinoma ex-pleomorphic adenoma. Carcinosarcoma is a very rare type of tumor and occurs when both epithelial and stromal cells undergo malignant transformation. This is in contrast with carcinoma ex-pleomorphic, which represents approximately 2-5% of salivary gland malignancies. In this type, only the epithelial component undergoes malignant transformation and the epithelial carcinoma simply arises from the epithelial component of a preexisting pleomorphic adenoma. It presents as a slow growing mass, which usually has been present 10-15 years and suddenly increases in size. Interestingly, malignant transformation increases from only 1.6% in tumors present less than five years to 9.5% in tumors present more than 15 years. This means that we need to continue to follow patients with pleomorphic adenoma as the predilection for malignant transformation increases the longer the patient has the lesion. It does have an aggressive natural history and a poor prognosis, with regional and distant metastasis. Histologically, there are malignant appearing cells adjacent to the typical appearing pleomorphic adenoma. Most commonly this will be in the form of an undifferentiated carcinoma or the adenocarcinoma. This tumor tends to be more aggressive than other salivary gland malignancies and about 25% will have cervical lymph node involvement on presentation. As you can see on this slide, it delineates normal adenoma tissue with the adjacent cells displaying increased mitotic features and epithelial transformation. Note the clear differentiation between the epithelial component with malignant transformation compared to the more benign adenoma on the left.
Core needle and incisional biopsies are not used due to risk of resultant fistula or tumor spillage causing recurrence. Traditionally, the FNA has been performed preoperatively for histologic confirmation as well as operative planning. Fine needle aspiration is the mainstay of therapy. One study by Tew in 1997 evaluated 195 FNAs and 159 intraoperative frozen sections for parotid tumors. They found that fine needle aspirations had a 90% sensitivity of malignancy, with the frozen section having 96% sensitivity for malignancy.
Imaging is also a vital component in the evaluation of salivary gland malignancies. Imaging is recommended for tumors that are large or fixed to the overlying skin, located in the deep lobe or parapharyngeal space, have possible extraglandular extension, involve the facial nerve, or have positive or questionable cervical node involvement.
Ultrasound can provide guidance in obtaining FNA specimens from the deep parotid or parapharyngeal space tumor. In the patients with cystic or heterogenous masses, ultrasound ensures sampling of the solid component and may also be helpful in biopsies of masses that are difficult to palpate. CT with contrast is routinely used preoperatively and provides excellent details of the tumor origin in relation to vascular and bony structures. It will also allow for surveillance of regional lymphatics. Currently, MRI with gadolinium is preferred and provides excellent soft tissue detail, which is superior to that of a CT scan.
Surgical excision is the mainstay for treatment of all primary salivary gland tumors. Postoperative radiation therapy is indicated when adverse histological features are present. I will also discuss some of the controversies about neck dissection as well.
As far as surgical intervention is concerned, complete resection of the tumor with clear margins is the clear goal of the surgery. Total parotidectomy is not mandatory for parotid gland malignancy and preservation of facial nerve is an important consideration. Preservation of the nerve and its branches should be achieved unless tumor actually encompass the nerve or one of its main branches.
In 1990, North et al presented a report of 87 patients with carcinomas of the major salivary gland, which was broken down into 70 parotid and 17 submandibular. From 1975 to 1987, they were treated at John Hopkins by surgery or surgery plus postoperative radiotherapy. For patients with previously untreated disease, 5 of 19 (26%) treated by surgery alone did experience local recurrence. This is in contrast to only 2 of 15 (4%), who had recurrence of the disease following surgery plus postoperative radiotherapy. The determinant five-year survival for patients receiving postoperative radiotherapy was 75% versus 59% for surgery alone. Dr. Chen in 2007 followed 207 patients retrospectively over five decades who received surgery without radiotherapy as a primary modality. In his case, he identified patients who were admitted for local regional recurrence with surgery alone to see which patients would potentially benefit from postoperative radiotherapy in the future. Based on these observations, his recommendation were that postoperative radiotherapy be initiated for patients with T3 or T4 disease, positive surgical margins, high-grade tumor histology or regional nodal metastasis.
Next, I will discuss the management of the neck in malignant salivary tumors. Clinically positive nodes have been treated with neck dissection with a type dictated on the extent of the nodal disease followed by postoperative radiation. However, there exists some controversy on the treatment of clinically negative necks or N0 necks. Options include observation, elective neck dissection, and elective neck radiation. In the literature, the rate of risk for occult nodal disease is wide and vague and deserves further investigation. With respect to how the N0 neck should be treated, the use of elective neck dissection versus radiation has not yet been made. Both types of treatments have their advantages and disadvantages but both modalities have not been compared in a clinical study one-on-one to establish superiority. However, when elective neck dissection is chosen, it should address levels II-IV. When elective neck radiation is selected, it is important to keep in mind those characteristics that predict occult metastasis are often independent indications for adjuvant radiotherapy to the primary tumor. Consideration should be given to this fact and when indications for adjuvant radiotherapy are established, the N0 neck can be treated with elected radiation instead of the neck dissection when desired. This treatment option is especially useful in elderly, debilitated patients. This is a graph from Armstrong’s article displaying nodal status and 5-year survival rate compared from the parotid and submandibular glands. In parotid carcinomas, the 5-year survival rate in a patient without neck involvement is 74% whereas in those with neck involvement, it drops considerably, to a 9% 5-year survival. The drop off is not as pronounced in the submandibular gland, but still is seen with 41% 5-year survival rate compared to only 9% in patients with nodal disease.
Armstrong et al studied the incidence of occult nodal metastasis. Of 407 patients with clinically negative necks, neck dissection was done in 90. Occult metastasis was found in 38% of these specimens. To attempt to determine incidence of metastasis related to prognostic factors, the researches report incidence percentage using all patients with the factor present, even if they did not undergo neck dissection. Here is a graph on that study. The cancers with high incidence are broken down by histologic subtype: 41% of epidermoid cancers, 18% of the adenocarcinoma, and 14% of the mucoepidermoid were found to have the highest incidence of occult lymph node involvement. It is important to note that in this study the mucoepidermoid carcinomas were not broken down into histologic subtypes, low-grade versus high-grade.
Stennert's group in 2003 reported on 160 consecutive of the patients over four years. At their institution, policy was to perform ipsilateral neck dissection on all major salivary gland cancers regardless of the tumor stage or histology. So, this allowed for evaluation of the true incidence of occult metastasis. This report found the highest incidence in adenocarcinoma which was seen at 17%, adenoid cystic cancer at 16%, and mucoepidermoid cancer at 13%. Of the 139 patients with the clinically negative necks, 45% had occult neck metastasis. Breaking that down by tumor grade, he showed that neck metastasis was found in 29% of T1, 54% of T2, 65% of T3, and 54% of T4. In 2005, Zbaren et al reported on primary carcinomas of the parotid in clinically negative necks. There were two treatment groups studied: one underwent neck dissection, the other was observed. No strict criteria were used and there was no significant imbalance between the two study groups. Interestingly, his report showed that occult metastasis was detected in 20% of the clinically negative necks who underwent elective neck dissection. Of the 8 of the 41 patients who underwent neck dissection, 5 had high-grade carcinoma and 3 had low-grade carcinoma. The primary carcinomas in these eight patients were classified as T2 in 4 patients, T3 in 1 patient, and T4 in 3 patients. Regional occurrence occurred in none of the patients with elective neck dissection and in seven patients in the observation group. Of the seven patients without neck dissection and neck recurrence, two patients were initially given adjuvant radiotherapy to the neck.
Now, I would like to follow-up on the case presentation. JP was seen in clinic two weeks postoperatively, and his wound was healing well. He had some mild right marginal mandibular weakness. Surgical pathology revealed a carcinoma arising in pleomorphic adenoma. He did have metastatic squamous cell carcinoma in one of four lymph nodes. He had no lymphovascular invasion or marginal involvement.
He had a dental consultation for teeth extraction and radiation-oncology consultation for initiation of radiotherapy, which he was scheduled to start at the end of September. Here is the surgical specimen taken intraoperatively. As you can see, the size of the tumor is very impressive. You can compare it with the preoperative scan or the preoperative picture from the clinic. Note the area of necrosis through the skin and overlying tumor involvement in the skin, which actually prompted him to seek medical attention.
In conclusion, malignancies of the major salivary glands represent a rare and diverse group of cancers. Knowledge about tumor staging and histologic grading is necessary for prognostic prediction, patient counseling, and treatment planning. Surgical treatment should be the primary therapy with removal of all gross disease as the surgical goal. The patient should receive postoperative radiotherapy to the primary sites if the tumor is stage III or IV, or if pathology shows positive margin or perineural invasion. There should be careful consideration given to the treatment of the neck with clinic disease as a definite indication for neck dissection and/or neck radiotherapy. The patients with clinically negative necks may have a higher incidence of occult metastasis than once previously thought. Consideration should be given for neck dissection in the N0 neck, especially if there exists a high incidence of occult neck metastasis based on histology, stage, or grade. There is strong evidence suggesting that radiotherapy is effective in controlling neck disease and consideration should be given to elective neck irradiation in lieu of neck resection in a certain population of the patients. Future studies are needed to compare outcomes of elective neck irradiation versus elective neck dissection versus observation in clinically negative necks.
Case Presentation:
JP is a 59-year-old male with no significant past medical history who presented to the Ben Taub General Hospital Otolaryngology Clinic with an enlarging right neck mass that had been present since he was 25 years of age. He described the mass as initially growing slowly, but increasing in growth rate recently with the development of intermittent dysphagia to solids. In addition, he recently noticed redness and break down of the overlying skin. He denied pain, fevers, chills, shortness of breath, hoarseness, otalgia and unintentional weight loss. He denied previous radiation exposure.
On exam, he was found to have a firm, poorly mobile right neck mass measuring 10cm x 12cm with erythema of the overlying skin with gross tumor invasion. There was no associated
lymphadenopathy palpable on examination. The remainder of his complete head and neck exam was normal.
Fine needle aspration was performed of the right submandibular gland which revealed atypical cells positive for neoplasia, most likely a pleomorphic adenoma. CT neck with contrast showed a 11.2 x 12.5 x 10.6 cm, partially necrotic right neck mass arising from the right submandibular gland without evidence of lymphadenopathy.
He underwent resection of mass with right submandibular gland excision. The patient did well postoperatively and was discharged home on POD#4 after drain removal. He was seen in clinic for follow-up two weeks after the surgery. His wound was healing well and had mild right marginal mandibular weakness. Surgical pathology results were as follows:
-Carcinoma arising in pleomorphic adenoma (carcinoma ex-pleomorphic adenoma)
-Metastatic SCCA in 1 of 4 lymph nodes
-No lymphovascular invasion or margin involvement
He was scheduled for a dental consultation for teeth extraction, as well as, radiation oncology consultation for initiation of radiotherapy.
Bibliography
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Stennert E, Kisner D, Jungehuelsing M, Guntinas-Lichius O, Schroder U, Eckel HE, Klussmann JP. High incidence of lymph node metastasis in major salivary gland cancer. Arch Otolaryngol Head Neck Surg 2003;129:720–723.
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Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery
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Last modified: May 12, 2008