Case 4 -

Mucoepidermoid Carcinoma, Low Grade of Parotid Gland Bruce M. Wenig, M.D. Mary S. Richardson, D.D.S., M.D.

History: A 36 year old Hispanic male presented with recurrent right parotid gland swelling. The lesion had been biopsied on numerous previous occasions. Gross Findings: Received for an intraoperative consult was a "superficial lobe" of parotid which consisted of an oval shaped soft fragment of tissue with a smooth encapsulated surface. Macroscopic examination revealed a cut surface of what appeared to be normal salivary gland tissue. The cut surface was inked one color and the remaining smooth encapsulated surface was inked a different color. The specimen was bisected along the long axis. The cut surface showed a centrally located, pinkish-tan 1.8 cm lesion with an irregular border and small glistening cysts. A thin cross section of the cut surface, which included the inked surgical margins, was submitted for frozen sectioning. Microscopic Findings: On low power examination, a central area of hyperchromatic cells is seen surrounded by a dense fibrous stroma. At the periphery of the dense connective tissue there are noted small duct formations which are confluent with several cystic spaces. At higher magnification, the hyperchromatic cells are observed to be densely aggregated lymphocytes. The dilated cysts and a few of the duct formations are lined by a thin multilayered epithelium. The epithelium consists of epidermoid cells, "intermediate" cells and focal aggregates of columnar mucin-secreting cells. In focal areas of markedly thickened epithelium, focal keratinization could be readily identified. Intraoperative Diagnosis: Mucoepidermoid carcinoma, low grade of parotid gland. Result : No further tissue was resected. Diagnosis on Permanent Section: Mucoepidermoid carcinoma, low grade of parotid gland Surgical margins negative for carcinoma. Discussion: Major salivary glands in particular the parotid glands, are the most common locations for salivary gland neoplasms to arise. Roughly one third of the neoplasms occurring in the major salivary glands are malignant while approximately half of the minor salivary gland tumors are malignant. Included among the more common and challenging tumors in the major salivary glands are benign mixed tumor (pleomorphic adenoma), mucoepidermoid carcinoma, salivary duct carcinoma, other frequently occurring major salivary gland tumors include Warthin's tumor (papillary cystadenoma lymphomatosum), acinic cell carcinoma and basal cell adenoma. Most tumors involving the major salivary glands have encapsulation and early tumor will have to be evaluated by intraglandular growth patterns. The parotid and submandibular glands have complete capsules while the sublingual gland capsule is incomplete. As with the minor salivary gland tumors, the diagnosis of benign and malignant is based on architecture and cytologic features. The advancing borders of the tumor, necrosis, neural invasion and extension beyond the confines of the gland are features strongly suggestive of malignancy. Useful features in the diagnosis of salivary gland tumors include: cytologic features of the individual cells and the composition of ductal structures architectural arrangement tissue response to tumor borders presence or absence of neural invasion Indications for Intraoperative Consultation in Major Salivary Gland Tumors The indications for intraoperative consultation in major salivary gland include: 1) Most major salivary gland neoplasms have had a fine needle aspiration biopsy (FNAB) and clarification or confirmation of the diagnosis is desired. Cases of major salivary neoplasms in which the FNAB is inconclusive will request intraoperative consultation for a diagnosis. 2) Evaluating margins of the resection to include the tumor distance from the surgical margin. 3) Determining if lymph node metastases are present: a few of the high grade salivary gland tumors will have a tendency for lymph node metastases (high grade mucoepidermoid carcinoma and salivary duct carcinoma). Surgeons Expectations of the Intraoperative Assessment of Major Salivary Gland Tumors The surgeon's expectations in the intraoperative assessment of minor salivary gland tumors include: 1) distinguishing between benign and malignant neoplasms 2) determine the specific type of malignancy; this will aid the surgeon in deciding extent of resection and surgeon may request the grade of the tumor (e.g. MEC). 3) assessing the adequacy of the surgical margins 4) assessing perineural invasion Most major salivary gland excisions involve either removing a lobe of the gland (parotid) or the whole gland (sublingual/submandibular gland tumors). Lymph nodes may be included depending on the type of tumor, histologic grade of tumor and particularly if tumor involves the parotid gland (paraparotid and intraparotid lymph nodes). Handling of Resected Tissue The majority of salivary gland tumors are located in superficial lobe of the parotid gland, therefore the lateral lobe is a common specimen. 1) Orient and ink the specimen, assessing the extent and location of tumor. 2) Determine if the tumor is within the confines of the glandular capsule or if it has infiltrated beyond the gland. 3) Assess whether the cut surface (glandular surgical margin) of the lateral lobe is involved by tumor. Remember the parotid "lobes" are only a designation of the portion of the gland that is lateral or medial to the facial nerve, there are no true "lobes". Pitfalls in the Intraoperative Assessment of Major Salivary Gland Tumors Major salivary gland tumors are uncommon. Due to this infrequency the pathologist may only occasionally see these tumors and thus the diagnosis may be problematic. Because the vast majority of major salivary glands are somewhat superficial in anatomic position, they frequently have received fine needle aspiration biopsy for the initial diagnosis for management of these lesions. The accuracy of frozen section diagnosis of salivary gland tumors is quite good and is comparable to the frozen section diagnosis accuracy at other body sites (94-96% accuracy). Whether speaking of minor salivary glands or major salivary glands, the most difficult diagnosis in salivary glands includes: distinguishing mucoepidermoid carcinoma from chronic sialadenitis, adenoiditis and cystadenoma recognizing with the possibility of cystic degeneration: (FNAB induced) within benign tumors such as pleomorphic adenoma and avoiding over diagnosing the necrosis and a malignancy. Mucoepidermoid Carcinoma (MEC) Mucoepidermoid carcinoma is a malignant neoplasm comprised of mucous-secreting cells, epidermoid cells, and "intermediate" cells in variable combinations. Clinical MEC, previously known as "mucoepidermoid tumor", is the most common malignant salivary gland neoplasm. Approximately one half of MECs occur within the parotid gland. In the submandibular glands and the parotid glands MEC is most often a solitary, painless mass. The duration of time from noticing the mass to the diagnosis ranges from months to decades with an average time frame of 1.5 years. The tumor is seen most commonly in the third through seventh decades with the average age being approximately 50 years of age. There is a slight female predilection. Approximately one third of the patients experience some form of tenderness, pain, drainage from the ipsilateral ear, dysphasia, and frequently trismus. Facial palsy is noted most often in high grade tumors. MEC is the primary histologic type of radiation induced salivary gland carcinoma. An increased incidence of MEC has been reported in children who have received high dose and low dose radiotherapy. MEC was seen in survivors of the atomic bombing of Hiroshima and Nagasaki , Japan . Pathology The microscopic appearance of MEC is somewhat variable. The tumor can appear as an ill-defined mass which may be partially encapsulated and have a rather firm consistency. There may be small cysts located peripherally which may contain mucous or perhaps a brown to red blood stained fluid. Reported tumors have ranged in size from 1-12 cm. Mucoepidermoid carcinomas of major salivary glands are partially encapsulated. The stroma is typically very dense and sclerotic with abundant chronic inflammatory cells and occasionally one can identify extravasated pools of mucin. The microscopic hallmark of MEC is the presence of three cell types; epidermoid cells, mucous cells, and intermediate cells that might be clear or columnar in some tumors. The "intermediate" cells are often round-to- oval with a overall size between ductal basal cells and polygonal epidermoid cells and have perinuclear halos. In most MECs intermediate cells outnumber the other two cell types. Mucous cells rarely compose more than 15% of the tumor and identification often requires histochemical stains (e.g.alcian blue, mucicarmine). This tumor occasionally is noted to have associated prominent lymphoid response which can aid in recognizing MEC. The grading of mucoepidermoid carcinoma is based on morphologic growth patterns and cytologic features. Items assessed are intracystic component (space occupied by cyst lumina of the total volume of tumor), mitotic rate, neural invasion, necrosis, and the presence of cellular anaplasia (Table 1). Low grade mucoepidermoid carcinomas are most often predominantly cystic and may have rare papillary excrescences which present as an intraluminal growth. Mitotic figures in low grade MECs are unusual and there is usually a lack of neural invasion necrosis or any cellular anaplasia. In contrast, high grade MECs contain more solid cellular growth areas and fewer cystic areas (less than 20%), perineural and intravascular invasion. The solid areas of high grade mucoepidermoid carcinoma are formed by the polygonal squamoid cells as well as "intermediate" cells. High grade MEC may have such a paucity of the mucous containing cells and special stains for mucin may be required to highlight the inconspicuous cells. In general, high grade mucoepidermoid carcinomas do not have much of an associated chronic inflammatory infiltrate as is seen with the low grade tumors. Awareness of a subvariant of MEC can be useful at frozen section. Clear cell mucoepidermoid carcinoma or "salivary gland nephroma" is characterized by clear cells with distinct cell membranes and eccentric small nuclei. The clearing of the cytoplasm is due to an accumulation of glycogen. An occasional oncocytic type growth or metaplasia, as well as focal spindle cell growth cell patterns have also been reported within mucoepidermoid carcinomas. In IOC a high grade MEC can resemble salivary duct carcinoma. The distinction can be made by locating the three cell types necessary for the diagnosis of MEC. Treatment and Prognosis The clinical behavior of MEC is strongly correlated to clinical stage, tumor grade, and the adequacy of treatment. When surgical margins contain tumor recurrence is much more likely. There are several grades or two tiered grading systems currently in use for mucoepidermoid carcinoma. The parameters for assessment are similar and all grading systems have a good predictability regarding outcome. In one study of mucoepidermoid carcinoma of major and minor salivary glands, 5% and 2.5%, respectively, of the low grade MECs either metastasized to regional lymph nodes resulting in death, compared with 55 and 80% of lymph nodes metastases for high grade tumors. Of special note is the lack of importance of tumor grade, unlike the parotid gland and minor salivary glands, in predicting MEC behavior of submandibular gland tumors. Investigators have suggested that the grade and staging of a submandibular gland tumor has less predictive value than those involving other sites. In stage I and II MEC of the parotid gland, it is recommended these tumors be treated by conservative excision and preservation of the facial nerve. Patients that have partial parotidectomies and clear margins of resection do as well as those patients who have received total parotidectomies. If a submandibular gland is involved by mucoepidermoid carcinoma, then the entire gland should be removed. Combined radiotherapy and surgery are the first treatment that may be indicated for tumors in this site because of its worst prognosis. Radical neck dissection is only recommended for patients who have T3 lesions and above. Pleomorphic Adenoma (PA) or Mixed Tumor (MT) This is a benign neoplasm composed of epithelial luminal cells and myoepithelial support cells. This tumor shows a unique and predominant differentiation towards the myoepithelial component of the tumor. Clinical PAs represent approximately 60% of benign neoplasms over all salivary gland sites. These tumors are usually solitary and infrequently a secondary or synchronous tumor may develop in a different gland. The most commonly associated salivary gland neoplasm is a Warthin's tumor but associations with mucoepidermoid carcinoma, acinic adenocarcinoma, and adenoid cystic carcinoma have also been described. The average age of patients with mixed tumors is in the fifth decade. PA also represents the most common salivary gland tumor in adults, children and adolescents. These tumors are typically slow growing, asymptomatic, and are discrete masses that can become very large when untreated. Of particular concern to the surgical pathologist are the recurrent tumors. The recurrent lesions frequently occur as multiple nodules and are less mobile than the initial tumors. In the parotid gland most PAs occur in the lower pole of the superficial (lateral) lobe of the gland. When PAs of the parotid gland present within the deep lobe, they tend to project into the parapharyngeal space and present as a lateral pharyngeal swelling. Facial paralysis is very rare and only occurs when the tumor is large or adjacent to the facial nerve to cause compression. Treatment of these tumors is complete surgical excision. The recurrence rates for five and ten years following complete excision are 96.6% and 93.7%, respectively. High recurrence rates are usually associated with any one of the following: enucleation of the tumor alone, rupture or spillage of tumor during removal, presence of pseudopodia or prominences beyond the main tumor, and presence of abundant chondroid myxoid stroma. In most instances, the recurrent tumor mimics the original histology, however with each recurrence there is an increased possibility for malignant transformation. Factors associated with this increased risk for malignant transformation include a long standing tumor, a tumor of the submandibular gland, large tumor size, zones of hyalinization, and areas of moderate mitotic activity. Pathology PAs generally range from a few millimeters to several centimeters in size. The masses are generally well circumscribed with a very thin compressed area of connective tissue at its periphery. They most often are solitary. In recurrent PAs, however, there are usually multiple nodules within the surgical bed. The tumor on cut surface appears white, glistening, has a rubbery consistency, and will bulge from the cut surface of the salivary gland. The PA's peripheral border is thinly encapsulated. This well demarcated border is a distinguishing characteristic for all benign salivary gland tumors. The cytomorphologic and architectural diversity of pleomorphic adenomas, however is quite extreme. These tumors have both epithelial and mesenchymal type elements thus a variety of histologic appearances are possible. The tumors may be composed primarily of myoepithelial plasmacytoid-like cells or exclusively myxochondroid stroma. The extracellular matrix is one of the more defining components to the PA. This stroma can take on a number of forms, chondroid (hyalin cartilage like substance), a poorly myxoid loose stroma, chondroid myxoid stroma, hyalinized stroma, and very rarely ossified stroma. Oftentimes, just the finding of a single group of polygonal stellate or glandular cells suspended within the matrix is very helpful in the diagnosis of PA. Often the groups are located at the peripheral zone subjacent to the capsule. It is suggested that the recurrence rate is much higher for those tumors that are composed primarily of the chondromyxoid stroma primarily due to the spilling of the very mucoid stroma during surgical excision. Pleomorphic adenomas that have very little extracellular stroma have often been referred to as "cellular pleomorphic adenomas". Despite the fact that these tumors do not have a myxoid chondroid stroma, they are recognized by the focal blending of the myoepithelial mantle cells with this cleared cytoplasm around a similar luminal cell. In contrast to the high recurrence rate of the myxoid chondroid stromas, those tumors with high cellular composition have been thought to be more prone to malignant transformation. Because of the superficial location of the major salivary glands fine needle aspiration biopsy (FNAB) changes may be seen. Frequently fine needle aspiration of the pleomorphic adenoma can result in a hemorrhagic track with micronecrosis. There may also be a florid proliferation of myoepithelium as well as prominent atypical squamous metaplasia. These findings certainly could be problematic on frozen section interpretation and be misdiagnosed as malignant transformation. Obtaining the history of whether the patient has had a prior FNAB could prevent such an error. Treatment and Prognosis The primary treatment for pleomorphic adenoma is complete surgical excision. There has been long standing debate whether a superficial (lateral) parotidectomy or an extracapsular dissection (lumpectomy) with a margin of normal tissue is more successful in reducing recurrent tumor and minimizing surgical complications. Studies have indicated that both procedures have a 0-8% recurrence rate. In contrast to the primary PA, recurrent mixed tumors are usually multifocal, poorly delineated from the surrounding connective tissue, and associated with scar tissue that can adhere to the facial nerve. This adherence to the facial nerve increases the risk for nerve damage during additional surgeries and generally recurrent PA is treated by a total parotidectomy including excision of scar tissue. When the submandibular gland is involved with a PA, the treatment of choice is a complete glandular excision. Cystadenoma Cystadenoma is a very rare epithelial tumor characterized by cystic proliferation of ductal epithelium. Clinical Approximately 50% of cystadenomas occur in the major glands. The average age for patients with cystadenomas is approximately 57 years of age. There is a female predilection. The age range of patients that have been reported is from 12-89 years of age. Cystadenomas represent only about 3% of all benign salivary gland tumors but they represent about 30% of benign major salivary gland tumors. Of all the cystadenomas, 45% occur in parotid and 7% occur in the submandibular gland. When these tumors occur in minor salivary gland, the most common site is the palate. They also have been reported in the lips and buccal mucosa. These tumors are generally slowly enlarging, asymptomatic and slightly compressible masses. Pathology The surface of cystadenoma shows multicystic spaces or a single, large dilated cyst. There may be a few nodular proliferations into the lumen of the cyst. The tumor is generally very well circumscribed with or without a fibrous capsule. Microscopically, these tumors are composed of a proliferation of ductal epithelium formed into single or multicystic structures which are buried in rather dense stroma. About 20% of these lesions are unilocular and of them about 66% have an intraluminal papillary growth. The luminal epithelium is most often cuboidal or columnar type and single or bilayered epithelium In rare cases, mucinous, oncocytic, and squamous cells can be focally evident. Most often, the cyst lining is attenuated. These cells are bland, the contents of the lumen is proteinaceous fluid, and mitoses are exceedingly rare. When a papillary tuft of epithelium is present, these lesions are referred to as papillary cyst adenomas. Cyst adenoma has some features similar to mucoepidermoid carcinoma including cystic and sometimes papillary proliferations and some variable cell types. In contrast to cyst adenomas, mucoepidermoid carcinomas reveal three cell types and have extraluminal solid islands of tumor that infiltrate adjacent tissue. Treatment and Prognosis Conservative therapy meaning complete surgical excision is necessary for these lesions. After complete excision they are unlikely to recur. Salivary Duct Carcinoma (SDC) Salivary gland carcinoma is a highly aggressive malignant salivary gland tumor that occurs primarily within the parotid gland. Clinical Salivary duct carcinoma most commonly affects the elderly with the peak incidence within the sixth and seventh decade of life. There is a marked male predominance. This tumor is known to frequently cause facial nerve dysfunction and often metastases to cervical lymph nodes before the diagnosis of the primary salivary tumor is made. Clinical presentation is generally an individual with a rapidly enlarging parotid mass associated with nerve palsy (42%), pain (23%), and cervical lymphadenopathy (35%). It is one of the most aggressive salivary gland carcinomas. In one series, the tumor mortality was as high as 77% at a mean followup of three years. Local recurrence has occurred in one third to two thirds of patients. Lymph node metastasis was present in two thirds of patients, and distant metastasis in 50-70%. The most frequent site for distant metastasis include; the lung, bone, and brain. Salivary duct carcinoma representing its own de novo tumor has also been described arising as a malignant component of a carcinoma ex pleomorphic adenoma. Pathology The microscopic appearance of salivary duct carcinoma is that of a poorly circumscribed solid mass which infrequently has cystic areas. The tumor is cream to tan colored. There are focal areas of punctate necrosis (comedo-like). The tumor most often extends beyond the confines of the normally identifiable salivary gland in the vast majority of cases. One of the most remarkable histologic features of this tumor is its resemblance to ductal carcinoma of the breast. Very often, SDC has a cribriform comedo-type necrosis pattern which is reminiscent of intraductal carcinoma of breast although paradoxically most of the component actually represents the base of tumor. The intraductal-like component shows the cribriform, papillary or cystic solid growth patterns with very prominent comedo necrosis. Infiltrative growth patterns are composed of single cords, nests, or single cells. Rarely cytoplasmic mucin is present. Mitotic figures are abundant. The stroma surrounding the neoplasm is densely fibrous and desmoplastic in appearance. In three quarters of these tumors vascular invasion and perineural invasion can be easily identified. Treatment and Prognosis Various studies have suggested that tumor size smaller than 3 cm is associated with a variable prognosis but this was not confirmed by other studies. It appears that none of the recognized histological parameters are of prognostic significance. The immunohistochemistry of this tumor is of interest with positive staining for GCDFP and HER2NEU as do breast carcinomas; however they are estrogen receptor negative. In regards to hormone receptors, studies have been shown that the cells will stain for androgen receptors and some have progesterone receptors that are rarely positive. Among the things included in the differential diagnosis for this lesion are metastatic breast cancer, high-grade mucoepidermoid carcinoma, and cystadenocarcinoma. High-grade mucoepidermoid carcinoma can resemble salivary duct carcinoma especially in a frozen section setting with marked artifactual distortion of the tissue. The mixture of cellshowever, such as epidermoid cells and goblet cells, is not seen in salivary duct carcinoma, and the zones of extensive necrosis are unusual for mucoepidrmal carcinoma. Table 1. 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