Molecular Biomarkers in Salivary Gland Neoplasms

Salivary gland neoplasms are relatively rare, accounting for approximately 5% of head and neck cancers worldwide.¹ These neoplasms pose a diagnostic challenge to pathologists, as morphologic features are overlapping, even between low- and high-grade neoplasms. Notably, a significant number of salivary gland tumors harbor specific genetic alterations.² While salivary gland tumors have historically been diagnosed through morphology and immunohistochemistry, the identification of recurring genetic alterations—both mutations and structural rearrangements—now serves multiple clinical purposes: facilitating diagnosis in complex cases, informing surgical and targeted therapy decisions, evaluating treatment response, determining clinical trial eligibility, and providing prognostic insights.^3–5

Diagnostic Methodology

Fine needle aspiration (FNA) cytology serves as the primary initial diagnostic tool for salivary gland lesions, with reporting standardized through the Milan System for Reporting Salivary Gland Cytopathology, which also provides malignancy risk assessments.^6,7 For surgical specimens, the World Health Organization Classification of Head and Neck Tumors offers comprehensive guidelines, cataloging more than 30 distinct epithelial salivary gland tumors.⁸

While distinctive morphological patterns can definitively diagnose many salivary gland neoplasms, cases involving high-grade transformation or overlapping features present significant diagnostic challenges. In such instances, clinicians can use an array of ancillary testing, including immunohistochemical staining, fluorescence in situ hybridization (FISH), RNA in situ hybridization (RNA ISH)^9,10, polymerase chain reaction (PCR), and next-generation sequencing (NGS). These techniques identify specific genetic alterations that not only aid in diagnosis but also provide valuable insights into prognosis and treatment response. (Table 1)

Table 1. Established genetic alterations in salivary gland neoplasms.^2,5,11–15 High prevalence genetic alterations in specific salivary gland entities and those with diagnostic or therapeutic importance are highlighted in bold font.

Diagnostic Biomarkers

Certain gene fusions are highly specific for salivary gland neoplasm types and may be used to aid in the diagnosis of these entities. NR4A3 gene alterations are highly specific for acinic cell carcinoma. ^16,17 MYB and MYBL1 gene fusions are highly specific for adenoid cystic carcinoma.^18–20 CTNNB1 mutations are common in basal cell adenoma, while CYDL1 mutations are more prevalent in basal cell carcinomas.^21,22 The EWSR1::ATF1 gene fusion is specific for clear cell carcinoma in the salivary gland.^23,24 RET fusions, particularly NCOA4::RET, are characteristic for intraductal carcinoma.²⁵ CRTC1/3::MAML2 fusions are considered diagnostic for mucoepidermoid carcinoma.^26-30 PLAG1 and HMGA2 gene fusions are highly specific for pleomorphic adenocarcinoma and carcinoma ex pleomorphic adenoma, but can also be seen in carcinomas with epithelial-myoepithelial morphology.³¹ ETV6 gene fusions aid in the diagnosis of secretory carcinoma.^32,33 PRKD1 p.E710D mutations and PRKD1/2/3 gene fusions may help aid in differentiation between polymorphous adenocarcinoma and other salivary gland tumors.^34,35 NTRK gene fusions are present in the overwhelming majority of secretory carcinomas.³⁶

Emerging Predictive Biomarkers and Therapeutic Targets

Androgen receptor (AR) gene alterations and overexpression are present in most salivary duct carcinomas and can also be observed in acinic cell carcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma.³⁷ Patients with these tumors may benefit from androgen deprivation therapy, which includes receptor antagonists, as well as luteinizing hormone- releasing hormone agonists.^38–40 The prognostic significance of AR expression in specific salivary gland carcinomas is challenging to evaluate, primarily due to the rarity of AR-negative salivary duct carcinomas. However, in general, tumors that are metastatic or unresectable tend to have a poorer prognosis.⁴¹

Most HER2/ERRB2 amplified salivary gland neoplasms are salivary duct carcinomas.⁴² Although there is no established consensus for treating HER2 positivity in these tumors, patients have benefited from treatment protocols similar to those used for breast cancer, including anti-HER2 therapies alone or in a combination with chemotherapy or immunotherapy.⁵ HER2/ERBB2 gene amplification and TP53 mutations are associated with poor prognosis in salivary duct adenocarcinoma.⁴³

TRK inhibitors are approved for adults and children with solid tumors harboring NTRK fusions, regardless of tumor type and without acquired resistance mutations. Patients with NTRK fusion positive salivary gland neoplasms, for example secretory carcinoma, may also qualify for these therapies, which have shown durable clinical benefits in multiple studies.⁴⁴ Additionally, second-generation TRK inhibitors are currently under development.⁴⁵ In certain disease indications, the presence of NTRK fusions may suggest a more favorable prognosis. For instance, salivary gland secretory carcinomas with NTRK fusions have been associated with a low recurrence rate and excellent overall disease-free survival.⁴⁶

BRAF inhibitor therapy, either alone or in combination with MEK inhibitors, has shown promise in small studies and case reports involving salivary gland carcinomas, with patients primarily demonstrating partial response and evidence of tumor regression.^5,47,48 The presence of BRAF mutations in salivary gland tumors has been associated with increased disease recurrence and mortality.⁴⁹

RET fusion-specific and ALK fusion-specific targeted inhibitors have significantly impacted the treatment of lung cancer, thyroid cancer, and other tumor types.^50–52 Given the efficacy and high specificity of these novel therapies in tumors harboring these gene rearrangements, patients with salivary gland carcinomas may also benefit from these therapeutic advancements.^53,54 Overall, RET fusion alterations in salivary gland cancers are associated with a shorter overall survival and shorter progression free survival than patients without the alteration.⁵⁵

MAML2 gene fusions may confer a favorable prognosis in mucoepidermoid carcinoma. CRTC1::MAML2 fusions, in particular, are being investigated as a therapeutic target, with current preclinical trials investigating the efficacy of NOTCH and EGFR inhibitors in tumors harboring this gene alteration.⁵⁶

In adenoid cystic carcinomas, gain of function NOTCH1 mutations, and loss of function SPEN mutations are associated with high grade transformation, aggressive disease, and worse outcomes.⁵⁷ NOTCH inhibitors have demonstrated promising results in clinical trials for patients with salivary gland tumors, including evidence of stable disease and increased progression free survival, as well as a high disease control rate.^58–60

EGFR overexpression in salivary gland tumors can occur through gene amplification or activating mutations and is associated with poor prognosis.^52,54 Drawing from successful treatment experiences in non-small cell lung and colon cancers, both tyrosine kinase inhibitors and monoclonal antibodies targeting these EGFR alterations show therapeutic promise.^61,62 The insulin-like growth factor 1 receptor (IGF-1R) pathway, linked to malignant transformation and metastasis across multiple cancer types, also warrants attention in salivary gland tumors.⁶² Notably, IGF-1R alterations may influence both prognosis and resistance to EGFR tyrosine kinase inhibitors, similar to patterns observed in non-small cell lung cancer.⁶² Additionally, several overexpressed receptors, especially receptor tyrosine kinases, may be important in salivary gland tumors. For example, c-KIT, VEGR, FGF1/2 are known to be overexpressed in many of these tumors and may aid in prognostication for patients, generally indicating a poor prognosis. These may serve as future biomarkers for salivary gland tumor patients.⁶²

HRAS mutations are identified at varying frequencies in several salivary gland neoplasms and may serve as a future biomarker for targeted therapy in these entities. Farnesyltransferase inhibitors are currently being investigated in patients with end-stage solid tumors that harbor HRAS mutations.⁶³ 

Challenges, limitations, future directions

The molecular characterization of salivary gland neoplasms, though rare and heterogeneous, is imperative given their limited treatment options. As these tumors are frequently driven by well-documented genetic alterations, molecular testing has emerged as an important tool for optimizing patient care. While various molecular methods exist, targeted NGS panels have become the standard in molecular laboratories. These panels excel at detecting both DNA and RNA-based cancer-associated alterations, enabling comprehensive analysis of mutations, translocations, and novel genetic changes from a single sample. Other emerging rapid techniques include RNA ISH, which has been reported to have high sensitivity and specificity in detecting MYB upregulation.^9,10

One challenge in salivary gland neoplasms is the frequently limited amount of tumor tissue or sample available for molecular testing. Setting aside a dedicated sample for molecular testing during collection procedures as part of routine practice may be a consideration to ensure specimen availability. Additionally, validating diverse sample types—including liquid cytology preparations, aspirate smear slides, and formalin-fixed paraffin-embedded tissue—can help maximize testing success.

Conclusion

Despite their rarity, molecular testing of salivary gland tumors both enhances diagnostic accuracy and enables personalized therapeutic strategies based on each patient's unique genetic profile.

References

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Gloria H. Sura, MD, FCAP, is board-certified by the American Board of Pathology in Anatomic and Clinical Pathology, Cytopathology, and Molecular Genetic Pathology. She is currently an assistant professor at The University of Texas MD Anderson Cancer Center, working in the Sections of Cytopathology and the Molecular Diagnostic Laboratory, Department of Anatomic Pathology, Division of Pathology and Laboratory Medicine. She completed her residency training in Anatomic and Clinical Pathology at Louisiana State University Health Sciences Center in New Orleans, LA, followed by fellowship training in Cytopathology and Molecular Genetic Pathology at Houston Methodist Hospital in the Texas Medical Center, Houston, TX. Dr. Sura’s research interests include preanalytics of molecular cytopathology testing, optimizing biomarker testing, and personalized medicine. Dr. Sura is a fellow member of the College of American Pathologists.

Jessica S. Thomas, MD, PhD, MPH, FCAP, is board-certified by the American Board of Pathology in Clinical Pathology and Molecular Genetic Pathology. She is an assistant professor of clinical pathology and genomic medicine with appointments at Weill Cornell Medical College, New York, and the Institute for Academic Medicine at Houston Methodist Hospital, Houston, TX. Dr. Thomas currently serves as co-medical director of the Molecular Diagnostic Pathology Laboratory and is the pathologist team lead for Diagnostic Molecular Oncology at Houston Methodist Hospital in the Texas Medical Center, Houston, TX. She is also program director of the Molecular Genetic Pathology fellowship, associate program director of Clinical Pathology for the Pathology Residency program, and medical director of the Houston Methodist Laboratory Science program at Houston Methodist Hospital. Dr. Thomas received her MPH degree in Health Education from the University of Southern Mississippi in Hattiesburg, MS, and her MD and PhD degrees from Louisiana State University Health Sciences Center in New Orleans, LA. She then completed a pathology residency and a clinical fellowship in molecular genetic pathology at Vanderbilt University Medical Center, Nashville, TN. Dr. Thomas is a fellow member of the College of American Pathologists and a member of the Personalized Healthcare Committee. Her clinical work and research interests are focused on molecular diagnostics, including molecular oncology and molecular infectious diseases, assay development and validation in the clinical laboratory, and trainee education in molecular pathology, clinical pathology, and laboratory management.