Salivary Gland Cancers: Biology and Systemic Therapy

Salivary gland tumors are a relatively rare and heterogeneous group of tumors with variable pathologic and phenotypic characteristics. The lack of clinical outcomes data and randomized controlled trials pertaining to them makes it difficult to formulate definitive treatment protocols that could help with making decisions regarding choice of therapy. Most studies involving systemic chemotherapy have not shown promising patient outcome results. With recent advances in molecular technology, however, it is now possible to identify specific genetic alterations and biomarkers as possible targets for therapeutic purposes. For example, in mucoepidermoid carcinomas, one of the most common types of malignant salivary gland tumors, a commonly seen genetic translocation [t(11;19)(q21;p13), which involves the CRTC1 and MAML2 genes] has been found to be associated with improved survival, making it a possible prognostic marker. Also, this translocation gives rise to a fusion protein that appears to render tumors highly sensitive to epidermal growth factor receptor (EGFR) inhibition. However, the results of phase II trials of EGFR inhibitors-as well as other targeted agents-in salivary gland tumors have been disappointing: there has been some disease stabilization but no objective responses. There remains a need for well-designed prospective clinical studies to improve management of these tumors.

Introduction

Salivary gland cancers are a rare, heterogeneous group of tumors that comprise less than 5% of head and neck cancers and about 0.5% of all malignancies.[1] They vary considerably in their phenotypic, biological, and clinical behavior, and they differ in their responsiveness to systemic therapies.

Parotid tumors encompass 80% to 85% of all salivary gland tumors;[2] almost 75% of these tumors are benign.[3] Submandibular gland tumors account for 10% of all salivary gland tumors, but almost half of these are malignant. Less than 1% of salivary neoplasms develop in the sublingual glands, but 75% to 80% of these are malignant. The remainder of salivary gland tumors arise in minor salivary glands, and most of these are malignant.[3]

Because of the rarity of salivary gland tumors, there is a paucity of randomized controlled trials evaluating management options for recurrent and metastatic disease. Most of our information comes from retrospective studies and isolated case reports. Also, most trials to date have been heterogeneous and have involved small numbers of patients, so informed decision making is difficult. This article reviews the pathology and current evidence on systemic therapies for the management of advanced salivary gland cancers that are not amenable to local therapy.

Histogenesis and Histopathology

Salivary gland cancers vary in their histologic appearances and patterns. They are believed to arise from progenitor cells residing within the ductal tributaries of salivary glands.[4] Salivary gland cancers can be divided into luminal (arising in acinar and ductal cells) and abluminal (arising in myoepithelial and basal cells) types. Differing contributions from these cell types produce a wide variety of histologically distinct patterns. Salivary gland cancers with predominant myoepithelial elements are considered to be biologically low-grade, as compared with those devoid of myoepithelium, which are considered high-grade.[5]

Salivary gland neoplasms (both benign and malignant) have been classified into 24 distinct histologic subtypes by the World Health Organization. Mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and adenocarcinoma represent the majority, accounting for more than 75% of these tumors (Table 1). A histologic grading system has also been proposed in which salivary gland cancers are divided into low, intermediate, and high grades based on their clinical behavior.[6] A high-grade tumor appears to portend a worse clinical prognosis in cases of MEC and adenocarcinoma.[7] However, there is no such spectrum of histologic behavior in the case of ACC, which has an overall poor long-term prognosis.[6]

Mucoepidermoid carcinoma (MEC)

MEC is the most common malignant salivary gland tumor in adults and children.[8] It derives from the main duct segment and is composed of basal, intermediate, and differentiated cells in varying combinations.[4] Histologic grading plays a role in the prognosis of MEC. High-grade MECs tend to recur locally and metastasize, while low-grade lesions, especially those arising from the parotid gland, metastasize rarely.[7,9] Interestingly, MECs arising in the submandibular gland tend to metastasize irrespective of their tumor grade.[7] The squamoid variant has a relatively worse prognosis.[10]

Adenoid cystic carcinoma (ACC)

ACC, seen most commonly in minor salivary glands, is the second most common malignant salivary gland carcinoma. Most molecular studies show that deletions and/or translocations on the long arm of chromosome 6 are consistently associated with ACC.[11,12]

Even though ACC is locally aggressive, with a tendency for perineural invasion, biologic progression is slow, and lymph node metastases are rare.[13] ACC has three principal growth patterns: tubular, cribriform, and solid. The grade of ACC is determined by the histologic architecture, with the solid form being more aggressive, while patients with tubular and cribriform growth patterns have longer survival.[14] Other factors linked with prognosis include clinical stage and p53 expression.[15]

Salivary duct carcinoma

Salivary duct carcinoma is an aggressive, high-grade malignancy that histologically resembles mammary duct cancers. It is most commonly seen in elderly white males[16,17] and arises in parotid glands. Histologically, the growth pattern is dominated by variably sized, round nodules with a cribriform, solid, cystic, or papillary architecture.[1] Clinically, lymph node metastases are found in 60% of cases, and up to 50% of cases present with distant metastases at the time of diagnosis.[1,18] Prognosis is dismal, with a median survival of 3 years from time of diagnosis.[16,17]

Polymorphous low-grade adenocarcinoma

Polymorphous low-grade adenocarcinoma is the third most common malignant tumor of the minor salivary glands, after MEC and ACC. This tumor histologically resembles ACC[19] and has a tendency to invade perineural spaces.[18] Local recurrence is seen in 9% to 26% of cases,[1] and adequate surgical excision[20] or postoperative radiation has been suggested to minimize local recurrence.[21]

Carcinoma ex pleomorphic adenoma

Carcinoma ex pleomorphic adenoma is defined as a carcinoma arising in a preexisting pleomorphic adenoma. The prognosis of carcinoma ex pleomorphic adenoma varies, with 5-year survival rates ranging from 30% to 96%, depending on the histology of the malignant component.[2] Other prognostic factors are extent of tumor invasion,[22] grade, tumor size, and lymph node status.[23] Carcinoma ex pleomorphic adenoma is known for frequent local recurrences and distant metastases.[24]

Acinic cell carcinoma

Acinic cell carcinoma is most commonly found to occur in the parotid gland and has an excellent prognosis, with a 5-year survival rate of about 90%.[25] Usually it is a low-grade tumor, but it can present as a high-grade tumor, with frequent mitoses, desmoplasia, and tumor necrosis.[26] Acinic cell carcinoma can also undergo transformation into high-grade adenocarcinoma or undifferentiated carcinoma, with loss of acinar differentiation.[1] Such tumors show lymph node and distant metastases in 50% of cases and require radical surgery along with adjuvant chemotherapy or radiation therapy.[27]

Acinic cell carcinoma usually has three predominant growth patterns: papillocystic, solid, and microcystic; however, these subtypes do not correlate with outcomes. A histogenetic classification has been proposed that divides acinic cell carcinomas into ductular, acinar, and ductulo-acinar forms and has some prognostic utility in predicting relapse-free survival.[28,29]

Genetic Abnormalities

Chromosomal translocations lead to the formation of chimeric fusion oncogenes, which may in turn lead to carcinogenesis. Chromosomal aberrations can be seen in almost all salivary gland neoplasms. Table 2 shows the most important chromosomal and genetic aberrations associated with salivary gland cancers, along with potential therapeutic targets. With the advent of new techniques in genetic sequencing, there is increasing information on these genetic abnormalities, which can potentially affect treatment in the future.

The most common genetic finding in MEC is the translocation t(11;19)(q21;p13), seen in approximately 55% of cases.[30] The fusion between the CRTC1 gene at 19p13 with the MAML2 gene at 11q21 results in formation of the MECT1-MAML2 fusion protein and causes an interruption of the Notch signaling pathway.[31] Patients with this translocation tend to have a better prognosis.[28,29] Patients with classic MEC who harbor this translocation have a 5-year survival rate of greater than 90%, as compared with 30% in patients with the squamoid variant, which lacks this translocation, suggesting its role as a prognostic marker.[10,28,29]

Recently a study showed that this fusion protein induced the upregulation of amphiregulin (AREG), which is a ligand of the epidermal growth factor receptor (EGFR). The CRTC1-MAML2 fusion protein activates the transcription factor CREB, which leads to the upregulation of AREG. AREG subsequently activates EGFR signaling in an autocrine fashion that promotes the growth and survival of MEC cells.[32] The cells that have this fusion protein have been shown to be highly sensitive to EGFR inhibition, thereby suggesting a potential role for EGFR-targeted therapies in patients with advanced, unresectable CRTC1-MAML2–positive MEC.[32,33]

Persson et al described a reciprocal translocation, t(6;9)(q22–23;p23–24), in ACC[11]; the translocation resulted in the formation of a fusion gene between the transcription factors MYB and NFIB and predicted a poor prognosis.[11,12] This translocation is seen in 28% to 100% of ACCs.[11,12] The fusion of the two genes induces transcriptional activation of the MYB target genes that are associated with cell cycle control (CCNB1, CDC2, MAD1L1), apoptosis (API5, BCL2, BIRC3, HSPA8, SET), and cell growth and angiogenesis (MYC, KIT, VEGFA, FGF2, CD53).[34] Another associated finding is the deletion (1p32-p36), which also serves as a marker for poor prognosis and is seen in approximately 44% of ACCs.[35]

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has recently been implicated in tumorigenesis, especially in human epidermal growth factor receptor 2 (HER2)-negative salivary duct carcinomas, with mutations in PIK3CA or deletions of PTEN in a proportion of this subtype.[36-39]

Pleomorphic adenoma has been shown previously to harbor gene fusions involving PLAG1 and HMGA2 oncogenes.[40] More recent studies have identified a role for amplification of HMGA2 and MDM2 exons on chromosome 12q, as well as amplification of ERBB2 (HER2), in malignant transformation of benign pleomorphic adenoma to carcinoma ex pleomorphic adenoma.[41] Early events in this malignant transformation also include expression of p53 protein and c-erbB2.[42,43] These findings suggest that reactivation of p53 function by using inhibitors of MDM2, such as MI-219, may be promising in the treatment of patients with MDM2 amplification.[44]

DNA promoter methylation has been found to have a role in the silencing of tumor suppressor genes and may contribute to carcinogenesis in salivary gland carcinomas as well. In a series, it was seen to be more common in salivary duct carcinoma than in MEC or ACC.[45] DNA promoter methylation is also thought to play a role in the conversion of pleomorphic adenoma to carcinoma ex pleomorphic adenoma, with DNA methylation seen in about 65% of these transformations.[46]

In contrast to the previously mentioned subtypes of salivary gland tumors, ACC has not been shown to have any pathognomonic gene fusion or mutation. The only molecular studies available are in mice models; in these, both the Wnt and mTOR pathways are constitutively activated by the conditional inactivation of the APC and PTEN tumor suppressor genes, thereby leading to formation of tumors similar to human ACCs.[47] In one study, treatment of tumor-bearing mice using the mTOR inhibitor rapamycin led to complete regression of tumors. This finding, along with the immunohistochemical evidence of activated mTOR signaling in human salivary ACCs, indicates that mTOR inhibitors such as rapamycin and temsirolimus could have a role in the treatment of such tumors.[47]

Molecular Biomarkers and Potential Targets for Therapy

Increased understanding of the molecular and hormonal profiles of salivary gland carcinomas has led to interest in studies of targeted therapy. The rates of expression of biological markers differ in the various studies performed, partly owing to differences in histology and staining methods (Table 3). Most of the studies have looked at overexpression of EGFR, HER2, vascular endothelial growth factor (VEGF), and c-kit.

c-kit

Kit is a transmembrane cell surface receptor encoded by the c-kit gene, which is associated with the regulation of cell migration, differentiation, and proliferation.[4] Several studies have shown that c-kit, a downstream target of transcription factor MYB, is expressed in the majority of ACCs.[48,49] Rao et al recently reported c-kit amplification in the subcentromeric region of chromosome 4q.[35] Studies targeting c-kit have not shown any benefits in patients with advanced ACC, even though it is overexpressed in such patients.[50,51] Further studies are required to determine the biological role of c-kit in salivary gland tumors and the utility of targeting this molecule.

EGFR

The incidence of EGFR overexpression has varied in ACC in different case series, ranging from 0% to 37%.[52,53] However, no EGFR mutations or amplifications have been identified in ACC, questioning the role of EGFR-targeted therapy in ACC.[53] On the other hand, some salivary adenocarcinomas have been found to have both EGFR overexpression and EGFR mutations, suggesting its role in potential therapeutic targeting in such patients.[54] As mentioned earlier, MECs with the CRTC-MAML2 fusion protein have a higher sensitivity to EGFR inhibition; this suggests a potential role for EGFR-targeted therapies in patients with the CRTC-MAML2 fusion protein who have advanced, unresectable disease.[32,33]

HER2

HER2 overexpression and/or HER2 gene amplification is seen in up to one-third of patients with MEC and even more frequently in patients with salivary duct carcinoma,[55] thereby suggesting its role as a potential therapeutic target in these tumors.[56] HER2 expression in ACC, on the other hand, is rare.

Androgen receptor

Nasser et al reported high expression of androgen receptors in salivary duct carcinomas.[57] Thus, there may be a role for antiandrogen therapy in this particular subset of patients.

Other biomarkers and targets

Transcription factors MYB and NFIB may prove to be potential therapeutic targets, although it is difficult to develop direct inhibitors to transcription factors.[33,40] Some studies have also shown a role for the fibroblast growth factor receptor (FGFR) signaling pathway in maintaining hematopoietic progenitor cells in a proliferative and undifferentiated state, thus suggesting its role as a potential therapeutic target.[58]

Lately, mutations in RAS pathway genes have been implicated in some cases of head and neck ACCs, suggesting a possible role of the BRAF inhibitor vemurafenib in patients with activating BRAF kinase mutations.[59] Another novel therapeutic approach utilizes the TRKC/NTRK3 pathway and its inhibition by TRKC kinase inhibitor AZD7451 and has been shown to inhibit growth in ACC-derived xenograft models, thus suggesting a potential therapeutic use.[60]

Systemic Treatment

In patients with salivary gland tumors, systemic therapy is usually reserved for those with rapid disease progression or advanced or incurable disease. It can also be used in patients with recurrent disease that is not amenable to surgery and/or radiation therapy. However, none of the studies have shown a definitive survival advantage with systemic therapy, making its role generally palliative.

Chemotherapy

There is a lack of adequate trials studying chemotherapy in the treatment of patients with salivary gland tumors, owing to the rarity and histologic heterogeneity of these tumors. Published trials have enrolled small numbers of patients with varying histology and number of prior systemic therapies; the proportion of patients with distant metastatic disease has varied as well. All these differences have affected the ability to gauge the real effectiveness of therapy.[5] The most commonly studied chemotherapeutic agents have been cisplatin and cisplatin-based regimens, which have demonstrated modest response rates and an unclear survival advantage.

In an Eastern Cooperative Oncology Group (ECOG) phase II trial of single-agent paclitaxel in 45 patients with malignant salivary gland cancers, 8 partial responses (25.8%) were seen among the 31 patients with MEC or adenocarcinoma.[61] No responses were seen in patients with ACC. Median survival in the entire cohort was 12.5 months. A systematic review also failed to find any significant activity of paclitaxel in the treatment of malignant ACC.[62] A phase II trial of single-agent gemcitabine showed disease stabilization for ≥ 6 months in 11 of 21 patients with advanced ACC but no objective responses in any of the patients.[63] However, not all patients in this study had disease progression at study entry, which could confound interpretation of the results.

A phase II trial of gemcitabine in combination with either cisplatin or carboplatin in 33 patients with advanced, metastatic, or locoregionally recurrent salivary gland cancer demonstrated 1 complete response and 7 partial responses across all histologies.[64] The median survival for all 33 eligible patients was 13.8 months, with a 1-year overall survival rate of 57%.

Various other chemotherapy regimens have been evaluated in salivary gland tumors but have shown little survival advantage.

Molecular targeted therapy

Increased understanding of molecular signaling pathways has led to the identification of various potential therapeutic targets. Although several phase II trials have investigated therapeutic agents correlated with some of these targets and the role of these agents in salivary gland carcinomas, most showed prolonged disease stabilization but very few objective responses (Table 4). Many of these trials did not require evidence of disease progression prior to enrollment, thereby limiting the interpretation of their results.[50,51,53,56,65-70]

The understanding that c-kit is overexpressed in most ACCs led to two phase II trials of the c-kit inhibitor imatinib in advanced ACC.[50,51] Both trials failed to demonstrate an objective response to imatinib, suggesting a lack of predictive value for c-kit overexpression in ACC. Ghosal et al conducted a phase II trial of the combination of imatinib and cisplatin in 28 patients with advanced ACC.[65] Nineteen patients had stabilization of their disease, with median time to progression and overall survival of 15 months and 35 months, respectively.

EGFR is often overexpressed in ACC and MEC, leading to trials looking at the role of agents targeting this pathway. Gefitinib, an orally acting EGFR tyrosine kinase inhibitor, was evaluated in a phase II trial.[66] Among the 36 evaluable patients (18 with ACC and 18 with non-ACC), no objective responses were observed. Eleven patients had disease stabilization, which was maintained for at least 16 weeks in 5 patients. Cetuximab, a human-murine chimeric monoclonal antibody to EGFR, was recently tested in a phase II study.[67] Among the 30 patients enrolled (23 with ACC and 7 with non-ACC), no objective responses were observed. Twelve patients with ACC and 3 with non-ACC histology had disease stabilization for a median of 6 months.

The anti-HER2 monoclonal antibody trastuzumab was studied in a phase II trial that enrolled 14 patients with advanced salivary gland cancers that overexpressed HER2.[56] One of the 3 patients with MEC had an objective response, with disease stabilization for over 45 weeks. Another case report was recently published that suggested a potential role for trastuzumab in salivary duct carcinoma.[71]

Lapatinib, an oral dual tyrosine kinase inhibitor of EGFR and HER2, was studied in a phase II trial involving patients with advanced salivary gland cancers who expressed EGFR and/or HER2.[53] Of the 36 evaluable patients, none demonstrated an objective response. Seventy-nine percent of the patients with ACC and 47% of the patients with non-ACC salivary gland tumors showed disease stabilization, and 36% had stable disease for over 6 months. Since disease progression was one of the prerequisites for enrollment in this study, disease stabilization could be a true drug effect.

Inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway has been suggested as a potential therapeutic target in ACC.[72] In an ECOG phase II trial of the NF-kB proteasome inhibitor bortezomib, no objective responses were seen in 21 evaluable patients with incurable ACC.[68] Disease stabilization was seen in 15 patients, with a median progression-free survival of 6.4 months.

Sunitinib, a multi-target inhibitor of VEGF receptor, c-kit, platelet-derived growth factor receptor (PDGFR), ret proto-oncogene (RET), and FMS-like tyrosine kinase 3 (FLT3), was studied in a phase II trial in patients with advanced ACC.[69] No objective responses were seen among 13 assessable patients, but 11 patients had disease stabilization, 8 patients had stable disease ≥ 6 months, and 2 patients had progressive disease as best response. Median time to disease progression was 7.2 months. Drug toxicities were seen in 50% of patients, and 3 patients had to discontinue participation in the study due to adverse effects.

Sorafenib, a multi-kinase inhibitor, was evaluated in a phase II trial that included 23 patients with advanced ACC.[70] Two patients had an objective partial response, with median progression-free survival of 11.3 months and overall survival of 19.6 months. The limiting factor, however, was drug toxicity, with 57% of patients experiencing grade 3 adverse events.

The FGFR signaling pathway has been investigated in an ongoing phase II trial of dovitinib, a multi-receptor kinase inhibitor of FGFR pathway–mediated angiogenesis.[73] Of the 19 evaluable patients, 2 have shown partial responses and 9 have shown disease stabilization to date. A phase II study of dovitinib (NCT01678105) is being conducted by the Ontario Clinical Oncology Group in patients with advanced and recurrent ACCs to help discern the role of this agent. A few case reports have shown benefit with the use of temsirolimus, an inhibitor of the PI3K/Akt/mTOR pathway in patients with salivary duct carcinoma.[74]

Hormone therapy

Although there are reports of androgen receptor overexpression in salivary duct carcinoma, no phase II trials have evaluated the role of anti-androgen therapy. Most available data are in the form of isolated case reports involving patients with ACC who were treated with tamoxifen[75,76] or with salivary duct carcinoma treated with anti-androgens.[77,78]. Hence, the use of antihormone therapy in salivary gland tumors remains to be elucidated.

Conclusions

Salivary gland cancers are a rare, heterogeneous group of tumors, and the lack of adequate studies evaluating therapeutic options makes it difficult to formulate standard treatment regimens. With advances in molecular and genetic technology, various genetic abnormalities have been identified.

Recently, there has been a spike of interest in new molecular therapies for advanced salivary gland carcinomas, leading to many phase II trials. While some studies show disease stabilization, true objective responses are uncommon. These disappointing results indicate a critical need for carefully designed, prospective, randomized trials with good predictive markers, in order to improve patient outcomes. In the meantime, the role of systemic therapy remains palliative, and it is mostly used to treat patients with recurrent or advanced metastatic disease.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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