34.1
Pleomorphic Adenoma
Pleomorphic Adenoma
Pleomorphic adenoma (PA) is an enigmatic tumor with a variety of names, including adenoma multiforme and benign mixed tumor. It is one of 15 benign epithelial tumors of the salivary glands as described by the 2017 World Health Organization (WHO) classification, and the most common benign tumor of the salivary glands, comprising 45–60% of all salivary gland tumors. More than 80% of PAs occur in the parotid gland, although they can occur in any of the salivary glands, major and minor, including unusual locations such as the nasal cavity, base of the tongue, palate, and trachea. It comprises 53–68% of benign tumors in the parotid; 44–68% of submandibular tumors; and 33–43% of minor salivary gland tumors. They can occur at any age, more commonly in women between the ages of 40 and 60. The incidence is 4.29/100,000, based on a Danish population study.
In the major salivary glands, PAs appear as a painless, firm, well-demarcated and mobile mass that can gradually grow or reach a growth plateau. In the minor salivary glands, this tumor may be less mobile as in the palate or nasal cavity. Multifocality and satellite lesions have been a subject of investigation and discussion; there is great variability in these findings with the notion of multifocality being overestimated. There are also reports of monoclonality of multifocal lesions indicating separation from a primary tumor. In cases of superficial lobe PAs, satellite lesions have not been found in the deep lobe when total parotidectomy has been performed. Bilateral PA has been observed with a very low incidence.
Histologic Characteristics
Pleomorphic adenoma’s name is derived from the presence of both epithelial and mesenchymal components in all of these tumors ( Fig. 34.1.1 ). The expression of these components can be variable giving rise to different subtypes of tumor, which include myxoid (stromal-rich), cellular (parenchyma-rich), or classic (balanced ratio myxoid:cellular). The variable presence of epithelial elements form tubular or solid structures and the stromal areas can contain myoepithelial cells along with chondroid, fibrotic, or osseous components. Glycosaminoglycans (hyaluronic acid and chondroitin sulfate) are secreted by the epithelium, which creates the myxoid and chondroid matrix that separates the cells from each other. It has been shown that the epithelial and myxoid elements are monoclonal and are therefore derived from the same precursor cell.
Capsule
Understanding capsular characteristics is key in management of PAs. It is not clear whether the capsule of PA is continuously produced as the tumor grows or it is fibroconnective tissue that stretches and is compressed by the growth of tumor. The capsule of PA can be thick in some areas, thin in others and absent at times. The fibrous capsule can be penetrated or invaded by the tumor. Smaller tumors tend to have a thicker capsule.
Capsule Nomenclature
See Fig. 34.1.2 .
Incomplete Capsule
Incomplete capsule describes areas where there is an absence of fibroconnective capsule and either the tumor sits adjacent to or extends into the surrounding salivary tissue or fat. Incomplete capsule is found to be present in 33–41.8% of parotid PAs, while submandibular PAs have been reported to have a much lower incidence of capsular breach. Mantsopoulos et al. saw no areas of incomplete capsule in their sample of 72 submandibular gland PAs. Minor salivary gland PAs also have incomplete capsules and have been noted to have offshoots into the capsule and in close proximity to mucous membranes. A higher incidence of incomplete capsule is noted in the myxoid PAs (28% of surface area), as compared with the cellular type (4%). The thickness of the capsule of PA varies from 5 µm to 250 µm, with myxoid PA being at the lower end (5 µm) of the thickness and cellular PA at the higher end (250 µm). Although most studies have shown the deep lobe tumors to have a thicker capsule in comparison with the superficial PAs, in their study, Zbären and Stauffer did not see a difference.
Capsule Penetration
Capsule penetration occurs when tumor cells infiltrate the capsule in finger-like projections or herniations, without separation of the infiltrative process from the main tumor by a fibrous band or capsule. They are at times described as tumor buds or nodular protrusions. This is why these tumors may appear grossly to be lobular. It is more common in the cellular subtype (as it is the cellular component infiltrating the capsule). It is seen in 26% of parotid PA specimens; the size of the tumor does not affect its incidence.
Pseudopodia
Pseudopodia is PA cellular tumor nodule that is separated from the main tumor body by a fibrous band but still contained within the main tumor capsule or in contact with it ( Fig. 34.1.3 ). The incidence in the parotid is 28–54%. The incidence is much lower in submandibular PAs at 15.8%. Zbären and Stauffer found this to be more common in cellular and classic subtypes, while others did not find a correlation. There is no relation between the size of the tumor and presence of pseudopodia.
Satellite Nodules
Satellite nodules are tumor masses or nodules separated from the main body of the tumor within normal salivary or fatty tissue; they represent an independent focus of PA with its own capsule without any connection to the main tumor ( Fig. 34.1.4 ). They may develop as an independent focus of PA or as progression of a tumor bud from a capsular breach or pseudopodia that ultimately separates and becomes independent. The monoclonality of satellite lesions and main tumor mass gives credence to the latter. Maximal distance between satellites and main tumors were found to be between 5.0 mm and 8.5 mm. The incidence in the parotid gland was 13–28% without any correlation to histologic subtype, while there was a direct correlation between size and presence of satellites (statistical difference between tumors <2 cm and those >4 cm). In the submandibular gland, the incidence is again far less, at 4.2%.
Diagnosis of Pleomorphic Adenoma
Pleomorphic adenomas are generally slow growing, painless, well-demarcated and mobile (when in a major salivary gland). As in-office surgeon-performed ultrasonography (SP-US) is becoming more commonplace for the head and neck surgeon, the accuracy and utility is improving. The features that are significantly associated with malignancy include extraparenchymal extension, irregular borders, hypervascularity, infiltration, and lack of deep enhancement. Ultrasound alone is able to accurately detect a PA with an 80% sensitivity and an 86% specificity.
Fine needle aspiration cytology’s (FNAC) utility has been questioned due to the incidence of false-negative results. In two series, the false-negative rate (postoperative finding of a malignancy) was 4–7%. Other studies show the diagnosis of PA via FNAC to be 97% sensitive and 98% specific. Combining SP-US with FNAC will improve accuracy, especially in cases of carcinoma ex-PA. Core biopsy can increase diagnostic accuracy with a larger sample size. Its true value is reserved for the clinical suspicion of hematologic malignancy but can be used when the FNAC results and clinical/imaging findings do not correlate; however, the potential for facial nerve injury must be considered.
Surgical Margins
Surgical margins are an important factor when discussing recurrent PA. While Witt found 100% of tumor resected (regardless of surgery extent, including total parotidectomy) had some degree of capsular exposure, Ghosh et al. saw a tumor margin of <1 mm, and a percentage of capsule exposure (>10%) as important causative factors. All recurrences occurred in patients that had widely exposed capsules, and none in the minimal exposure group; and when margins were <1 mm (18% recurrence) vs >1 mm (1.8%). In conclusion, minimizing capsular exposure and, when possible, getting a generous margin of healthy salivary tissue is highly recommended.
Tumor Rupture
Tumor rupture is also an immensely important factor. This occurs when there is a gross breach in the tumor capsule with potential spillage of tumor cells in the surgical field ( Fig. 34.1.5 ). Most studies that have taken tumor rupture into consideration find a direct relation with recurrence. Park et al. found a 14-fold increased (4% vs 30%) risk of recurrence when there is rupture. The widespread distribution of recurrent disease (see Chapter 41 ) makes curative treatment very difficult and often impossible, carrying with it a high risk of facial nerve complications and further recurrence, therefore the initial surgical approach must be sound, with expertise.
Metastatic Pleomorphic Adenoma
Metastatic pleomorphic adenoma (MPA) is a very rare tumor that is histologically indistinguishable from PA; however, it has metastasis at local and distant sites. It most commonly occurs in the parotid gland (74%), and less so in the submandibular gland (14.8%). Knight and Ratnasingham found 72.8% of cases to have a local recurrence of PA prior to MPA, with 37% demonstrating multiple local recurrences. Total surgical resection is the treatment of choice with no data available on adjuvant treatment due to rarity of the disease. Although the proliferation rate of these tumors is low, making it a relatively low-grade malignancy, multiple metastasis portends a poor prognosis, and prompt resection is warranted.
Molecular Genetics
There are known genetic alterations in PAs, the most common of which is a translocation at 8q12.1 (gene promoter swap), resulting in overexpression of PLAG1 (pleomorphic adenoma gene 1), which is part of a family of cell cycle progression-related proteins. HMGA2, on chromosome 12q, is an architectural transcription factor that regulates cell cycle regulator genes; fusion alterations of this gene have been found in PAs. Rearrangements in 8q12, are present in >50% of PAs; much less so in 12q14-15 region (10–15%). No genetic alteration has been identified in RPA in contrast to PA that brings it a step closer to carcinogenesis. While some groups have seen a persistence of PLAG1 and HMGA2 in carcinoma ex pleomorphic adenoma (CXPA), others have reported the absence of PLAG1 as a hallmark of malignant transformation; perhaps testing methodology plays a role in this discrepancy. Chromosomal gains, amplifications, gene fusions, and translocations in 8q, 12q, and loss in 17p are promoters of malignant transformation. Additionally, presence of HER2 (40%, mostly in SDCA) and EGFR (44%, both myoepithelial and SDCA) amplifications in CXPA are correlated with a poor outcome, while dual presence (23%) is indicative of a very aggressive subgroup. However, they also serve as targets for immunotherapy.
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Pleomorphic adenoma’s name is derived from the presence of both epithelial and mesenchymal components.
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Pseudopodia is less common in submandibular pleomorphic adenoma.
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Minimizing capsular exposure and, when possible, getting a generous margin of healthy salivary tissue is highly recommended.
34.2
Warthin Tumor
Warthin tumor (WT), also known as papillary cystadenoma lymphomatosum or adenolymphoma , was first described by Aldred Warthin in 1929, in two cases.
WT is the second most common benign tumor of the parotid gland, although it was reported the most common benign tumor in a series from Singapore. It has been associated with male gender and smoking and reported as multicentric in approximately 25% and bilateral in up to 15% of the cases. An increase in the incidence of WT in women was noted, possibly in association with an increased incidence of smoking. The vast majority of WTs occur in the parotid gland, although extra-parotid lesions have also been described. Incidence of WT is uncommon in the pediatric population.
Localization of WT in the parotid gland has rarely been discussed. Occurrence of WT in the deep lobe of the gland was found to be 4%, 3.7%, rare in a bi-institutional study of 122 patients, to non-existent in a study of 183 WT patients ( Fig. 34.2.1 ). The deep lobe of the parotid is considered to account for 20% of the glandular tissue, with a similar proportion of lymph nodes. Presumably, a similar proportion of superficial vs deep lobe WT could be anticipated. The reason for the tumor to be limited almost uniformly to the superficial lobe is unknown but could presumably be related to the etiology of this elusive entity. This localization of the tumor was suggested as an additional common characteristic of WT.
There is a great geographic and ethnic variability in the worldwide occurrence of WT. It is common in the Asian population but rare in Blacks. A significant number of our WT patients are from Jewish-Iraqi origin and the great majority are from the Iraqi-Syrian-Turkish region. WT is a rare occurrence in the African population, despite salivary gland tumors being a significant health problem in that continent.
The etiology and pathogenesis of WT is still unclear, with some evidence that even challenges its neoplastic nature by arguing in favor of it being a developmental abnormality, or is the result of an autoimmune reaction. The authors reported formerly on familial occurrence of WT and, while it is classically considered to be a non-genetic disease, recently we identified four siblings (two males and two females) with bilateral WT in a single inbred family. Moreover, >10 cases of WT were identified within that same inbred cohort, suggesting possible recessive heredity of tumor predilection. Homozygosity mapping identified a possible genomic locus for a disease-associated gene, and relevant potential disease-causing mutations within this locus, identified through next generation sequencing, are currently being evaluated by our team.
On gross pathologic examination, WT are usually encapsulated masses with a smooth or lobulated surface. Papillary cysts are commonly found on sectioning and contain mucoid, brown fluid. Solid gray tissue encapsulates white nodules of lymphoid tissue. Microscopically ( Figs. 34.2.2–34.2.4 ), the combination of papillae of eosinophilic epithelia that project into cystic spaces and lymphoid matrix is a distinct and pathognomonic histologic feature. The typical cystic lining is arranged in two cell layers of even rows. The apical or luminar tall columnar and basal cuboidal cells contain small dark nuclei and abundant granular pink cytoplasm (oncocytes). The granular eosinophilia of oncocytes is due to abundant mitochondria present in the cytoplasm. The histology of WT includes both an oncocytic epithelial component forming cystic spaces with papillary appearance and lymphoid stroma. These microscopic features may suggest that WT originates in salivary parenchyma inclusions trapped in the intra- and periglandular lymph nodes of the parotid gland.
The diagnosis of WT can be established by patient history, clinical examination, imaging, and cytology. Patients with WT usually present with an asymptomatic, slow-growing mass in the superficial lobe of the parotid gland, often at the angle of the mandible ( Fig. 34.2.5 ). Occasionally, patients may present with swelling, pain, and other inflammatory-like manifestations that may be secondary to an immunologic response. As was recently described, the evaluation of WT includes ultrasound-guided fine needle aspiration (FNA) with cytology characterized by the triad of oncocytes, lymphoid cells, and a proteinaceous background. The impact and importance of FNA in WT has been widely discussed and is valuable in the diagnosis of WT both in its high sensitivity and high positive predictive value and for the implications of establishing a definite diagnosis prior to considering surgery. Though highly accurate, FNA cytology may often falsely diagnose oncocytoma, lymphoma, squamous cell carcinoma, and may also be nondiagnostic. Also, although uncommon, FNA in WT may lead to infection in much higher incidence than in other parotid tumors and while this does not negate its common use, it should be taken into consideration. Frozen section was reported to have 100% accuracy rates. The uncommon incidence of WT in the deep lobe and in light of false-positive rates of FNA, re-evaluating a lesion in the deep lobe of the gland with FNA cytology of WT was suggested.
