Salivary Gland Malignancies

Neoneurogenesis

The study of perineural invasion (PNI) is an important biologic consideration for many cancers, especially for MSGTs such as ACCs. The molecular determinants of this mechanism of spread, which have only begun to receive attention in recent years, have yielded insights to view this spread pattern as an active and reciprocal interaction between malignant cells and peripheral nerves. Observations in other cancer sites currently suggest that PNI is the result of a mutual neurotropic interaction with cancer cells characterized by the release of various paracrine growth factors. As with neoangiogenesis, it is clear that the in-growth of nerve endings into a tumor may be stimulated by the tumor release of various neurotrophins, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and its receptor tyrosine kinase A (TrkA). Neurotrophin staining has been demonstrated to be present in ACCs. NGF and TrkA have both been correlated with the presence of perineural invasion. Recently the expression of neurotrophin-3 (NT3) and its receptor TrkC/NTRK3 was demonstrated in ACCs. These tumor-innervating nerve cells may release neurotransmitters that function as proliferative and promigratory signals for the tumor cells. Furthermore, nerve fibers are used as routes for tumor cell dissemination. For pancreatic carcinoma, detailed studies of serial sections have demonstrated that tumor cells can progress along branching nerve fascicles in a continuous fashion.

Therapeutically these insights offer the potential for the development of small molecule inhibitors, such as Trk tyrosine kinase inhibitors, especially for ACCs in hopes of addressing this pattern of spread. Importantly, radiation recently has been shown to impair PNI not only through direct cancer cytotoxicity but also with prophylactic treatment of the nerve, disruption of paracrine signaling preventing perineural spread in an animal model system. Such observations are important because they have potential radiotherapy treatment planning implications.

Mucoepidermoid Carcinoma

Mucoepidermoid carcinoma can be divided into high grade versus low grade or high, intermediate, and low grade with the treatment implication being that low-grade cancers did not need elective nodal irradiation. In a classic paper by Brandwein et al., 20 mucoepidermoid cancer slides were shared with five expert pathologists and they were asked to grade them using their own criteria as well as a proposed, standardized Armed Forces Institute of Pathology (AFIP) criteria. The average kappa for their own criteria and proposed AFIP standardized grading was only 0.49 and 0.61. It is tantalizing to think that genetic information could help us more accurately subtype these cancers.

In 2003, the recurrent and hallmark t(11;19)(q21;p13) translocation involving CRTC1 at 19p13 and MAML2 at 11q21 was described by several groups demonstrating it to be a key pathogenic event that underlies the development of mucoepidermoid carcinomas (MECs). Although diagnostically useful, there was conflicting data from other groups on the prognostic significance of the MAML2 rearrangement.

The identification of the CRCT1/3-MAML2 translocation, in some instances, might represent the most direct pathway to a confident diagnosis of the so-called ‘Warthin-like’ mucoepidermoid carcinoma, a low grade variant of mucoepidermoid carcinoma that shares morphologic and immunohistochemical overlap with a benign Warthin tumor ( Fig. 43.1 ). Identification of the characteristic fusion offers not only the promise of future risk stratified treatment approaches but also insights into the development of novel therapeutic targets. For example, unfavorable fusion-positive MECs are believed to have acquired further somatic mutations conferring increased invasiveness such as deletion in the CDKN2A (p16) gene.

It has been observed that low/intermediate mucoepidermoid cancers have fewer copy-number-aberrations when compared with high-grade mucoepidermoid cancers. Translocation-negative tumors were found to have more copy-number-aberrations, suggesting that mucoepidermoid cancers be divided into t(11:19)(q21: p13) translation-positive tumors with no or few chromosomal mutations versus translation-negative tumors with multiple positive chromosomal aberrations.

The parotid is a purely serous gland, therefore no mucin should be produced. A number of mucins were expressed in mucoepidermoid cancers and the difference in the expression of various mucins may also aid in more accurate grading of mucoepidermoid cancers.

Mutation Analysis: Dysregulation in Growth Factor Receptors

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (erbB2 or HER2/neu) are members of the EGFR transmembrane receptor family and, when activated, transduce mitogenic signals. Several studies have reported high immunohistochemical expression levels that may be more dominantly expressed in non-ACCs. However, the clinical significance of EGFR protein overexpression remains controversial with some multivariate analyses demonstrating both an independent association with poor survival and others demonstrating no independent association with poor survival.

Similarly, erbB2 overexpression has been reported for MSGTs. These include strong overexpression in some MECs and in salivary duct carcinomas (SDCs), but rarely for ACCs. Univariate and multivariate independent prognostic significance has been reported for erbB2 overexpression. Agulnik et al. suggest that greater clinical activity with the dual EGFR and erbB2 inhibitor lapatinib may be possible in tumors with both high EGFR and erbB2 expression and that erbB2 may be especially important. Recently, patients with SDCs and erbB2 amplification treated with a trastuzumab-containing regimen containing other targeted agents based on actionable mutations were found to have improved survival compared with patients who did not have actionable mutations. Identifying subgroups of patients more dependent on erbB2 signaling may be important in further defining the therapeutic benefit with erbB2 inhibition because tailoring therapies based on molecular abnormalities may be have therapeutic benefits.

Pathology

The classification of SGTs is primarily based on microscopic morphologic criteria, with ancillary testing, such as immunohistochemical staining, and more recently, the utilization of fluorescence in situ hybridization (FISH) to detect characteristic chromosomal rearrangements in support of the morphologic interpretation. Two general classification systems of salivary gland tumors have been recognized and includes the AFIP and the World Health Organization (WHO). In 2017 the WHO updated their 2005 classification of salivary gland tumors ( Table 43.4 ). Several benign epithelial and mesenchymal lesions of the salivary glands are newly included with the fourth edition of the WHO Classification of Head and Neck Tumors. Among epithelial lesions, sclerosing polycystic adenosis is a rare but benign lesion that can be multifocal and occasionally recur. Intercalated duct hyperplasia is highlighted here as it may represent a precursor salivary lesion, particularly to basal cell adenoma and possibly to epithelial-myoepithelial carcinoma. Newly included mesenchymal lesions of salivary gland include hemangioma, lipoma, and nodular fasciitis. Mammary analog secretory carcinoma originally described in 2010, is a new classification within the fourth edition of the WHO classification, and the name is now simplified to secretory carcinoma. Prior to its recognition as a distinct salivary gland tumor, examples of secretory carcinoma were most likely designated a variant of acinic cell carcinoma, mucoepidermoid carcinoma, or adenocarcinoma not otherwise specified when encountered in practice. Secretory carcinoma is morphologically analogous to secretory carcinoma of the breast, and both the salivary and breast carcinoma share the ETV6-NTRK3 gene fusion. Although secretory carcinoma is generally regarded as a low-grade salivary gland malignancy, prognosis can be influenced by stage, and the presence of high-grade transformation, which has been described in rare cases. Accurate identification of secretory carcinoma may be important if a selective TRK inhibitor is under therapeutic consideration.

In addition to new tumor entries, several conceptual changes regarding salivary gland tumor classification were introduced in the 4 ^th edition of the WHO classification. The name polymorphous low-grade adenocarcinoma (PLGA) has now been shortened to polymorphous adenocarcinoma (PAC). The rationale for modification of the tumor name lies first in recognizing that not all polymorphous “low-grade” adenocarcinoma behave in such a fashion. Removing the default terminology “low-grade” from the name is important in allowing the pathologist to characterize examples, although uncommon, where the tumor deviates from the typical low-grade characterization. Although highly controversial, the name change to PAC additionally serves as a unifying diagnosis between two previously separate entities; “PLGA” and the morphologically and molecularly similar tumor known as cribriform adenocarcinoma of minor salivary gland (CAMSG). Although the latter is regarded as having a higher incidence of regional metastases, the identification of shared genes within the same family suggests “PLGA” and “CAMSG” may be variants within a spectrum. As always, polymorphous adenocarcinoma may have a microscopic appearance that can on small biopsy samples mimic that of adenoid cystic carcinoma. The indolent clinical course more commonly described with PAC makes accurate distinction from adenoid cystic carcinoma important.

Changes to the section on pleomorphic adenoma include the addition of the new subheading metastasizing pleomorphic adenoma, which despite the name, is reclassified from a malignancy because its histologic pattern is identical to benign pleomorphic adenoma. Nonetheless, metastasizing pleomorphic adenoma should still be regarded as having the potential for aggressive biologic behavior. In the classification of infiltrating carcinoma ex-pleomorphic adenoma it is important to note that the terminology “carcinoma ex pleomorphic adenoma” should no longer be utilized as a stand-alone diagnosis. The malignancy identified as arising in association with the pleomorphic adenoma component should additionally be classified. The most commonly recognized subtypes arising ex-pleomrphic adenoma are salivary duct carcinoma, myoepithelial carcinoma, epithelial-myoepithelial carcinoma, and adenocarcinoma not otherwise specified ( Fig. 43.2 ).

Also new in the WHO 4 ^th edition is incorporation of the terminology “high-grade transformation” (HGT), which represents the preferred terminology over “dedifferentiation.” Acinic cell carcinoma, adenoid cystic carcinoma, and epithelial-myoepithelial carcinoma are tumors in which the phenomenon of HGT is well known. A tumor with HGT is expected to show more aggressive behavior.

Practically, histologies may be categorized as high-grade histologies with at a greater risk of nodal and distant metastases or low-grade histologies with a lower risk of nodal metastasis. The former includes high-grade MEC, high-grade adenocarcinoma–NOS, carcinoma ex pleomorphic adenoma, SDCs, certain variants of carcinoma ex pleomorphic adenoma, the presence of HGT and squamous cell carcinomas. Low-grade histologies include low-grade MECs, acinic cell carcinomas, secretory carcinoma, and PAC. In adenoid cystic carcinoma, tubular and cribriform patterns of growth are cytologically low grade, but identification of solid pattern growth portends a more aggressive course. An intermediate group has also been described consisting of intermediate MECs.

For MECs, the histologic grading has been shown to be of prognostic significance. High-grade disease also increases the risk of nodal metastasis sufficient to warrant elective management (e.g., neck dissection). Despite this, the risk of nodal metastasis with low grade (LG) and especially intermediate grade (IG) can still be significant. Ozawa et al. reported that, using the Goode (a.k.a. AFIP) grading schema, low- and intermediate-grade MECs had nodal metastases in 24% and 30%, respectively. High-grade (HG) MECs demonstrated nodal metastases in 56% of patients. In the modified Healey grading schema, lymph node involvement was 0% (LG), 22% (IG), and 72% (HG). T category also is associated with an increased risk of nodal metastasis for both major and minor salivary gland MECs. T1 HG disease may be at low risk for nodal metastasis in major salivary glands, that is, anatomic sites not involving the mucosa.

Pathways of Spread

When considering all histologies together, the risk of lymph node metastasis is increased with T3 and T4 disease, involvement of a pharyngeal site and high-grade MECs, adenocarcinoma–NOS, and salivary duct carcinoma. Similar observations have been reported with T stage, anatomic site, and histology ( Table 43.5 ). For minor salivary glands, the density of the lymphatics in the anatomic site has a significant influence on the risk of nodal metastases. In general, cancers arising within the oropharynx or nasopharynx have about a 60% incidence of lymph node metastasis compared with 5% to 10% for hard palate and paranasal sinus sites. Minor salivary gland cancers arising within the tongue and floor of the mouth have an approximately 40% incidence of lymph node metastasis; nasal cavity, buccal mucosa, and lip have a 15% incidence or less. For minor salivary gland tumors, independent risk factors for nodal involvement include male gender, T3-T4 stage, pharyngeal site of primary malignancy, and high-grade adenocarcinoma or high-grade mucoepidermoid carcinomas.

ACCs at the primary site have a predilection for PNI as a unique pattern of local disease extension. ACCs occur most commonly in the palate and frequently spread by PNI. PNI may be seen in more than 50% of cases and spread may occur in both directions along the nerve. Growth along the nerve has been shown to have “skip” areas of involvement and noninvolvement; however, “skip” metastases along nerves have not been substantiated in studies of squamous cancers of the skin and careful anatomic studies of adenoid cystic cancer may yield to the same conclusion.

The risk of distant metastases is increased with the presence of lymph node metastasis, skull-base involvement, and high-grade histology. Common distant metastatic sites, which include lung, liver, and brain, are also associated with the histologic grade.