Benign Neoplasms of the Salivary Glands

Genetic Factors

Gene fusions and chromosomal arrangements define a subset of salivary neoplasms. Cytogenetic analysis of more than 400 pleomorphic adenomas has demonstrated that over 50% of cases harbored translocations involving chromosome 8q12. The target gene of 8q12 translocations is the pleomorphic adenoma gene 1 (PLAG1) , which becomes activated by the chromosomal rearrangements. PLAG1 -driven tumors are characterized by upregulation of insulin-like growth factor (IGF) and WNT signaling pathways. Additional rearrangements have also been identified in chromosome 12q14-15, involving the high-mobility group AT-hook2 gene (HMGA2) , which functions as a transcription regulator. The 12q14-15 translocations have been found in approximately 15% of pleomorphic adenomas. Both pleomorphic adenomas and carcinoma ex-pleomorphic adenomas harbor PLAG1 and HMGA2 fusions. As such, these genomic alterations cannot be used to exclude malignancy. However, high-grade tumors tend to demonstrate more genomic instability and subtype-specific alterations such as HER2 amplification in salivary duct carcinoma. Additional genomic alterations observed in benign salivary gland neoplasms include CTTNB1 mutation and 16q12-13 deletion in basal cell adenomas. Basal cell adenomas can rarely be associated with hereditary syndromes, namely the Brooke-Spiegler syndrome, an autosomal dominant disease characterized by the development of multiple adnexal cutaneous neoplasms.

Radiation

Increasing evidence suggests that exposure to ionizing radiation may increase the risk of developing tumors of the salivary glands. In 1996, the Radiation Epidemiology Branch of the National Cancer Institute published a study on the risk of developing salivary gland tumors among atomic bomb survivors. The study indicated a higher radiation-related risk of developing both benign and malignant salivary gland tumors compared with the general population. Dose-response analyses found statistically significant increases in risk for both cancer and benign tumors with increasing radiation “dose” from the bomb. The risk was higher for malignant tumors, especially mucoepidermoid carcinoma. Among those with benign neoplasms, Warthin tumor showed the highest dose-response–related risk.

Radiation therapy to the head and neck, especially if it encompassed the salivary glands, may also be a risk factor in the development of salivary gland tumors. Modan and colleagues reported a 4.5-fold increase in the incidence of salivary gland cancer and a 2.6-fold increase of benign tumors among people exposed to low-dose scalp irradiation compared with matched controls. The mean length of latency period until tumor development was 11 years for malignant tumors and 21.5 years for benign growths.

Other Environmental Factors

Warthin tumor is strongly associated with cigarette smoking, and the risk decreases after smoking cessation. Recent studies have not demonstrated an association between Epstein-Barr virus and benign salivary neoplasms.

Fine-Needle Aspiration Biopsy

Fine-needle aspiration biopsy (FNAB) has been widely recognized and well established as a diagnostic tool in salivary gland neoplasms. Numerous studies have reported high sensitivity, specificity, and positive predictive value for FNAB. The overall sensitivity ranges from 85.5% to 99%, and the overall specificity ranges from 96.3% to 100%. In general, diagnostic accuracy is higher for benign salivary gland tumors. However, in up to 5% of samples, a malignant neoplasm can yield a cytologic diagnosis of benign neoplasm, demonstrating that false-negative results do occur. The accuracy of FNAB depends greatly on the experience of the cytopathologist and the overall volume of salivary neoplasms evaluated at a particular institution. The most common source of diagnostic error of FNAB is inadequate sampling, which occurs at a rate of approximately 5%. When initial FNAB is nondiagnostic, Brennan and colleagues have shown that repeat FNAB can have a high success rate (82%) in eventually providing a diagnosis. The use of ultrasound-guided FNAB may be of help when it is difficult to obtain a representative sample, and it enhances the overall diagnostic accuracy of the technique.

Given its histologic diversity, challenges exist in the cytopathologic diagnosis of salivary gland neoplasms. One contributing factor was the lack of a uniform reporting system to guide clinical management. Recently, an international panel of experts in salivary gland cytology, the American Society of Cytopathology, and the International Academy of Cytology jointly proposed an evidence-based reporting system known as the Milan System for Reporting Salivary Gland Pathology. The goal of the new classification system was to facilitate standardized reporting and improve the overall effectiveness of FNAB across institutions. Six categories were defined and shown in Table 84.3 . Their respective associated risks of malignancy are also shown in Table 84.3 . The “nonneoplastic” category includes specimens lacking evidence of a neoplastic process such as those demonstrating inflammatory, metaplastic, and reactive processes. In this category, clinicoradiologic correlation is essential to ensure that the specimen is representative of the lesion of interest. “Atypia of Undetermined Significance (AUS)” is a heterogeneous category where a neoplasm cannot be excluded. It may include lesions with reactive atypia or poorly sampled neoplasms and likely requires repeat FNA or surgery for definitive diagnosis. The “Benign Neoplasm” category is reserved for clear-cut benign neoplasms and has a low associated risk of malignancy of less than 5%. The “Salivary Gland Neoplasm of Uncertain Malignant Potential (SUMP)” category was developed for cases in which a neoplasm can be seen but a diagnosis of a specific entity cannot be made and a malignant neoplasm cannot be excluded. This category has an estimated risk of malignancy of 35%.

Several specific issues can lead to diagnostic dilemmas. The most frequent problems involve variations in the expected cytology of pleomorphic adenoma. Also, there are several benign-malignant “look-alike” pairs of lesions. The first of these is related to small cell epithelial neoplasms of low nuclear grade; the most frequent problem is between basal cell adenomas and adenoid cystic carcinoma, particularly the solid type. The next area contrasts mucoepidermoid carcinoma with its cytologic mimic, benign salivary gland duct obstruction. The final difficulty in salivary gland aspiration contrasts large-cell epithelial lesions of low nuclear grade: oncocytic proliferations and acinic cell carcinoma.

FNAB is safe, simple to perform, and relatively inexpensive. Heller and colleagues performed a study to determine the impact of FNAB on patient management and found that FNAB resulted in a change in the clinical approach in 35% of the patients. Examples of such changes in the planned management included avoiding surgical resection for lymphomas and inflammatory masses and adopting a more conservative approach with benign tumors in elderly and high-risk surgical patients. FNAB also allows for better preoperative counseling of patients regarding the nature of the tumor, the likely extent of resection, management of the facial nerve, and the likelihood of a neck dissection. Such information is not only important in treatment planning but also helps alleviate an already high level of anxiety in patients and their families. In a similar study, Sharma and associates also demonstrated the impact FNAB had in altering the clinical decision making, which obviated the need for surgery in 40% of cases.

The possibility of tumor seeding is a commonly cited argument against the routine use of FNAB in patients with salivary gland tumors. To address these issues, Mukunyadzi and colleagues reviewed 94 resected salivary gland masses for infarction, hemorrhage, needle-tract tumor seeding, and fibrosis after FNAB. They concluded that FNAB with a 25-gauge needle is safe and does not significantly alter the histologic diagnosis, because tissue effects did not preclude accurate diagnostic interpretation in any case.