MicroRNA copy number alterations in the malignant transformation of pleomorphic adenoma to carcinoma ex pleomorphic adenoma.

OBJECTIVE: This study used array comparative genomic hybridization to assess copy number alterations (CNAs) involving miRNA genes in pleomorphic adenoma (PA), recurrent pleomorphic adenoma (RPA), residual PA, and carcinoma ex pleomorphic adenoma (CXPA). MATERIALS AND METHODS: We analyzed 13 PA, 4 RPA, 29 CXPA, and 14 residual PA using Nexus Copy Number Discovery software. The miRNAs genes affected by CNAs were evaluated based on their expression patterns and subjected to pathway enrichment analysis. RESULTS: Across the groups, we found 216 CNAs affecting 2261 miRNA genes, with 117 in PA, 59 in RPA, 846 in residual PA, and 2555 in CXPA. The chromosome 8 showed higher involvement in altered miRNAs in PAs and CXPA patients. Six miRNA genes were shared among all groups. Additionally, miR-21, miR-455-3p, miR-140, miR-320a, miR-383, miR-598, and miR-486 were prominent CNAs found and is implicated in carcinogenesis of several malignant tumors. These miRNAs regulate critical signaling pathways such as aerobic glycolysis, fatty acid biosynthesis, and cancer-related pathways. CONCLUSION: This study was the first to explore CNAs in miRNA-encoding genes in the PA-CXPA sequence. The findings suggest the involvement of numerous miRNA genes in CXPA development and progression by regulating oncogenic signaling pathways.

Differential expression of TRKB tyrosine kinase in the two histological types of parotid salivary duct carcinoma with cancer aggressiveness.

Parotid salivary duct carcinoma (SDC) is a rare and aggressive parotid gland carcinoma (PGC). SDC has two origins: de novo and ex pleomorphic adenoma (SDC ex PA); however, because of its rarity, the clinical and molecular features of the two types of SDC are not sufficiently understood. Here, we studied the differences in their clinicopathological and molecular features using clinical specimens while comparing them to those of adenoid cystic carcinoma (AdCC), an intermediate-grade PGC. Clinicopathological analysis of tissues from patients with PGC revealed significant associations between histological types and malignant phenotypes, including nodal metastasis, recurrence, vascular invasion, and neural invasion, and revealed more malignant phenotypes of de novo SDC than of SDC ex PA. The de novo SDC showed a significantly higher frequency of intra-neural invasion (intra-NI) and vascular invasion than AdCC and SDC ex PA. PGCs with high intra-NI were significantly correlated with malignant phenotypes and survival rates. Recently, we observed the overexpression of tropomyosin receptor kinase B (TRKB), a receptor tyrosine kinase, in PGC cells. Here, immunohistochemical and clinicopathological analyses showed that TRKB was highly expressed in SDC cells, particularly de novo SDC cells, and was significantly associated with poor survival and highly malignant phenotypes, including intra-NI and vascular invasion. Collectively, these data show that TRKB expression is significantly elevated in PGC, particularly in de novo SDC, and can be one of the biomarkers of their aggressiveness.

Molecular Factors in Carcinoma Ex Pleomorphic Adenoma: Systematic Review and Meta-Analysis.

OBJECTIVE: Carcinoma ex pleomorphic adenoma (CXPA) is a rare malignant salivary gland tumor. Although multiple reviews have been published on salivary gland malignancies, it has been a decade since the last dedicated systematic review pertaining to CXPA alone was published. This study examines molecular factors in CXPA diagnosis. DATA SOURCES: MEDLINE, CINAHL, Embase, Scopus, Web of Science (BIOSIS), Cochrane CENTRAL, Health Collection (Informit), OpenDOAR, and GreyNet International. REVIEW METHODS: Systematic review and meta-analysis from inception to October 31, 2022 for all English language studies pertaining to "carcinoma ex pleomorphic adenoma." Predicted incidence of each biomarker was calculated with meta-analysis. Comparison against pleomorphic adenoma (PA) and salivary duct carcinoma (SDC) when reported within the same study are performed. Risk of bias performed with JBI tool for prevalence studies. RESULTS: Of 19151 unique studies undergoing abstract screening, 55 studies (n = 1322 patients) underwent data analysis. Biomarkers with >3 studies were p53, HER2, AR, EGFR, PLAG1, ERBB, ER, PR, HMGA2, p16, p63, a-SMA, RAS, PTEN, PDL1, BRAF, PIK3CA, and c-kit. Highest incidence was seen in AR, EGFR, p16, and p53. Significant differences were demonstrated compared with PA and SDC. There was high heterogeneity and overall high risk of bias within studies. CONCLUSION: Molecular factors are an area of interest in the diagnosis of CXPA. Our study results support examining CXPA as a discrete cohort in future targeted therapy trials. Laryngoscope, 134:1042-1053, 2024.

Pathogenesis Analysis of Salivary Gland Tumors Through the Expression of Programmed Death-Ligand 1 (PD-L1).

Pleomorphic adenoma (PA) is the most common salivary gland neoplasm, followed by Warthin's tumor (WT). In addition to its high frequency, PA also shows metastasis and transformation towards malignancy as carcinoma ex-pleomorphic adenoma (CXPA). While the histogenesis of WT remains unclear, especially given the presence of lymphoid stroma around the developing tumor and the immunological interaction between them. Immune escape is a carcinogenesis mechanism of tumors to avoid the host immune system by producing PD-L1. This study was conducted to determine whether there is an immune escape through the expression of PD-L1 in salivary gland tumors. The tissue sections of PA, CXPA, and WT were stained with Hematoxylin Eosin and immunostained with a rabbit monoclonal recombinant anti-PD-L1 antibody. We observed immunopositive PD-L1 on the cell membrane with or without cytoplasm staining. PA and CXPA expressed PD-L1, accompanied by an anomaly expression of CXPA in several spots at the salivary gland at the surgical border. Therefore, PD-L1 is one of the PA pathways to transform into CXPA through immune escape. WT expressed PD-L1 in the cytoplasm and lymphoid stroma but not on the cell membrane. It is interpreted as positive constitutive, which may have the function of increasing tumor cell growth, while overexpressed PD-L1 in lymphoid stroma is thought to be associated with a poor prognosis of the tumor and is suspected to transform into malignancy, such as B-cell Lymphoma.

Submandibular gland carcinoma ex pleomorphic adenoma with calcification.

We report an unusual case of carcinoma ex pleomorphic adenoma (CXPA) in the submandibular gland. The mass had a unique calcification. Panoramic tomography revealed sponge-like calcification. The central portion displayed heterogeneous high signal intensity on T1-weighted image (T1WI) and T2-weighted image (T2WI), and heterogeneously moderate signal intensity on a short-TI inversion recovery (STIR) image. The ADC was low (0.78 × 10-3mm2/sec). After surgical excision, a pathological examination revealed that the mass contained CXPA as a minor component. Tumor cells with large hyperchromatic nuclei and eosinophilic or clear cytoplasm proliferated in irregular small tubule formations or cribriform or Roman-bridge structures in hyalinized or focally ossified stroma. The entire mass was calcified, particularly in the central region. Taken together, the reduced T1 relaxation times were related to the surface effects of diamagnetic particles, which were observed at calcium particle concentrations of up to 30%. We report a CXPA with unusual sponge-like calcification, which appeared unusually hyperintense on T1WI due to a surface effect.

A rare case of epithelial-myoepithelial carcinoma ex pleomorphic adenoma of the parotid gland: Radiologic-pathologic correlation.

Carcinoma ex pleomorphic adenoma is a carcinoma that arises from a primary or recurrent benign pleomorphic adenoma. The prevalence of epithelial-myoepithelial carcinoma is low, and this histological type accounting for only 1% of all salivary gland tumors. Here, we report a rare case of Epithelial-Myoepithelial Carcinoma ex pleomorphic adenoma of the parotid gland with a radiologic-pathologic correlation.

Loss of BAP1 Protein Expression by Immunohistochemistry in the Salivary Duct Carcinoma Component of an Intracapsular Carcinoma ex Pleomorphic Adenoma of the Parotid Gland.

BACKGROUND: BRCA1-associated protein 1 (BAP1) is a tumor suppressor gene that is altered in a variety of neoplasms as well as in BAP1 tumor predisposition syndrome. BAP1 alterations are associated with aggressive behavior in some malignancies and may have treatment implications in future. We present the first documented case of loss of BAP1 protein expression by immunohistochemistry in the salivary duct carcinoma (SDC) component of an intracapsular carcinoma ex pleomorphic adenoma (CXPA) in the context of molecular loss of function of BAP1 in the neoplasm. METHODS: A woman of approximately 55 years of age presented with a deep parotid lobe mass, which was resected and found to be CXPA. BAP1 immunohistochemistry and next-generation sequencing was performed to further characterize the neoplasm. RESULTS: The neoplasm showed loss of BAP1 protein expression in the SDC component but retention in the residual pleomorphic adenoma (PA). Next-generation sequencing confirmed a BAP1 loss of function alteration in the neoplasm. CONCLUSION: This is the first documented case report of BAP1 protein expression loss in the SDC component of a CXPA. Future studies are needed to investigate the relevance of BAP1 alterations in SDC and CXPA, which may have prognostic and treatment implications.

Partial response to RC-48 as palliative treatment in a patient with locallocally advanced carcinoma ex pleomorphic adenoma harboring a HER2 mutation: a case report.

BACKGROUND: Carcinoma ex pleomorphic adenoma (CXPA) is a neoplasm of the salivary gland that causes 3.6% of salivary gland tumors and 12% of salivary gland malignancies. Its prognosis is determined by the histological progression beyond the adenoma capsule. CXPA is thought to be a malignant transformation of a primary or recurrent pleomorphic adenoma and is associated with both benign and malignant lesions. Salivary gland cancers represent a rare heterogeneous group of neoplasms with complex clinicopathological characteristics and distinct biological behavior. CASE DESCRIPTION: This case report summarizes the treatment of a 57-year-old male patient with CXPA of the left parotid gland, harboring HER2 amplification with poor prognosis. The overall survival of the patient has been > 3.5 years. The application and outcome of an immune checkpoint inhibitor and targeted therapy combination regimens in the treatment of CXPA carcinoma are discussed. CONCLUSION: Targeted therapy combined with immunotherapy has long-term clinical benefits and targeted therapy which has a high clinical response rate (immunotherapy + dual-targeting three-drug regimens) may present an ideal choice for the treatment of patients with rare and/or refractory tumors without compromising patient safety.

Novel Discovery of the Somatostatin Receptor (SSTR2) in Pleomorphic Adenomas via Immunohistochemical Analysis of Tumors of the Salivary Glands.

Reliable preoperative diagnosis between salivary gland tumor entities is difficult. In this monocentric retrospective study, we examined the somatostatin receptor 2 (SSTR2) status of salivary gland tumors after salivary gland tumor resection via immunohistochemistry (IHC), and stains were compared in analogy to the HER2 mamma scale. A total of 42.3% of all pleomorphic adenoma (PA) tumors (42 of 99, 95% confidence interval 32.5-52.8%) demonstrated ≥20% of cells displaying the SSTR2 as compared to just 1% of all other tumors (1/160, 95% CI 0.02-3.4%). The other tumor was a neuroendocrine carcinoma. PA had a higher intensity of SSTR2 staining, with 90.9% staining ≥ an intensity of 2 (moderate). Tumors with an intensity of SSTR2 expression equal to or greater than 2 had an 89.9% likelihood of being a PA (95% CI: 82.2-95.0%, AUC: 0.928). Only one Warthin tumor demonstrated a 'strong' SSTR2 staining intensity. No Warthin tumor showed a percentage of cells staining for SSTR2 above ≥20%. This result demonstrates consistent and strong expression of SSTR2 in PAs as compared to Warthin tumors, which may allow physicians to utilize radioligand-somatostatin analog PET CT/MR imaging to diagnose the PA. SSTR2 positivity, if shown to be clinically relevant, may allow peptide receptor radionuclide therapy in the future.

Extracellular matrix remodelling and stiffening contributes to tumorigenesis of salivary carcinoma ex pleomorphic adenoma--A study based on patient-derived organoids.

BACKGROUND: Salivary carcinoma ex pleomorphic adenoma (CXPA) is defined as a carcinoma that develops from benign pleomorphic adenoma (PA). Abnormally activated Androgen signaling pathway and amplification of HER-2/neu(ERBB-2) gene are known to be involved in CXPA tumorigenesis. Recent progress in tumour microenvironment research has led to identification that extracellular matrix (ECM) remodelling and increased stiffness act as critical contributing role in tumour carcinogenesis. This study examined ECM modifications to elucidate the mechanism underlying CXPA tumorigenesis. RESULTS: PA and CXPA organoids were successfully established. Histological observation, immunohistochemistry (IHC), and whole-exome sequencing demonstrated that organoids recapitulated phenotypic and molecular characteristics of their parental tumours. RNA-sequencing and bioinformatic analysis of organoids showed that differentially expressed genes are highly enriched in ECM-associated terms, implying that ECM alternations may be involved in carcinogenesis. Microscopical examination for surgical samples revealed that excessive hyalinized tissues were deposited in tumour during CXPA tumorigenesis. Transmission electron microscopy confirmed that these hyalinized tissues were tumour ECM in nature. Subsequently, examination by picrosirius red staining, liquid chromatography with tandem mass spectrometry, and cross-linking analysis indicated that tumour ECM was predominantly composed of type I collagen fibers, with dense collagen alignment and an increased level of collagen cross-linking. IHC revealed the overexpression of COL1A1 protein and collagen-synthesis-related genes, DCN and IGFBP5 (p < 0.05). Higher stiffness of CXPA than PA was demonstrated by atomic force microscopy and elastic imaging analysis. We utilized hydrogels to mimic ECM with varying stiffness degrees in vitro. Compared with softer matrices (5Kpa), CXPA cell line and PA primary cells exhibited more proliferative and invasive phenotypes in stiffer matrices (50Kpa, p < 0.01). Protein-protein interaction (PPI) analysis of RNA-sequencing data revealed that AR and ERBB-2 expression was associated with TWIST1. Moreover, surgical specimens demonstrated a higher TWIST1 expression in CXPA over PA. After knocking down TWIST1 in CXPA cells, cell proliferation, migration, and invasiveness were significantly inhibited (p < 0.01). CONCLUSION: Developing CXPA organoids provides a useful model for cancer biology research and drug screening. ECM remodelling, attributed to overproduction of collagen, alternation of collagen alignment, and increased cross-linking, leads to increased ECM stiffness. ECM modification is an important contributor in CXPA tumorigenesis.

Metastatic Myoepithelial Carcinoma Ex Pleomorphic Adenoma of the Sublingual Salivary Gland.

Myoepithelial carcinoma ex pleomorphic adenoma is a very rare malignant neoplasm of the salivary gland. Owing to its rarity, its clinical features and treatment are not well characterized. We describe a case of a patient who was referred to our department with a six-month history of a bulge on the right side of the floor of the mouth and a submandibular mass with progressive enlargement. The mass was resected, and an elective level I neck dissection was performed. Histological examination revealed myoepithelial carcinoma ex pleomorphic adenoma of the sublingual salivary gland. Thoracic computed tomography and biopsy revealed lung metastases. The patient died two years after the diagnosis.

Cytopathology of salivary gland myoepithelial carcinoma: A study of 13 cases and review of the literature.

INTRODUCTION: Myoepithelial carcinoma (MECA) is an infrequently recognized salivary gland (SG) neoplasm that commonly develops within a preexisting pleomorphic adenoma (MECA ex PA). Fine-needle aspiration (FNA) biopsy reports of this neoplasm are largely restricted to small series and single case reports. METHODS: Our cytopathology files were searched for examples of SG MECA/MECA ex PA having confirmatory histopathologic verification. Conventional FNA biopsy smears were performed, and exfoliative specimens processed using standard techniques. RESULTS: Thirteen cases from 9 patients (M:F = 3.5:1; age range: 36 to 95 years, mean age = 60 years) met inclusion criteria. FNA biopsy sites included parotid gland (4), trunk (2), scalp (2), and neck (2). Exfoliative specimens included pleural fluid (1), bronchial brushing (1), and bronchoalveolar lavage (1). Most cases were metastatic deposits (8; 62%), 4 were primary neoplasms, and 1 a local recurrence. FNA diagnoses were MECA ex PA (6; 46%), myoepithelial neoplasm (2), PA (2), basaloid neoplasm (1), atypical myoepithelial cells (1), and myxoma (1). Ancillary testing in 2 cases showed positive staining for myoepithelial markers. Cytologic features were that of a low-grade neoplasm composed principally of epithelioid/polygonal cells exhibiting minimal if any cytologic atypia. Myxoid and chondromyxoid stroma was often the dominant feature in MECA ex PA aspirates. CONCLUSION: In the primary setting, a cytologic diagnosis of MECA/MECA ex PA is extremely challenging if at all possible. Due to overwhelming amounts of stroma, the diagnosis may be challenging in some cases of metastatic MECA ex PA.

Heterogeneity and versatility of the extracellular matrix during the transition from pleomorphic adenoma to carcinoma ex pleomorphic adenoma: cumulative findings from basic research and new insights.

Pleomorphic adenoma (PA) is the most common salivary gland tumor, accounting for 50%-60% of these neoplasms. If untreated, 6.2% of PA may undergo malignant transformation to carcinoma ex-pleomorphic adenoma (CXPA). CXPA is a rare and aggressive malignant tumor, whose prevalence represents approximately 3%-6% of all salivary gland tumors. Although the pathogenesis of the PA-CXPA transition remains unclear, CXPA development requires the participation of cellular components and the tumor microenvironment for its progression. The extracellular matrix (ECM) comprises a heterogeneous and versatile network of macromolecules synthesized and secreted by embryonic cells. In the PA-CXPA sequence, ECM is formed by a variety of components including collagen, elastin, fibronectin, laminins, glycosaminoglycans, proteoglycans, and other glycoproteins, mainly secreted by epithelial cells, myoepithelial cells, cancer-associated fibroblasts, immune cells, and endothelial cells. Like in other tumors including breast cancer, ECM changes play an important role in the PA-CXPA sequence. This review summarizes what is currently known about the role of ECM during CXPA development.

Spectrum of salivary gland diseases: A 24-year single-institution retrospective study.

Introduction: Salivary glands are exocrine glands and are classified as major and minor salivary glands. Salivary gland pathologies are classified as neoplastic and non-neoplastic. The neoplasms of salivary glands can be benign or malignant. Aim: The aim of the study was to describe the frequency of various salivary gland diseases reported in our institution from 1997 to 2021. Methodology: This was a 24-year retrospective study of salivary gland lesions processed and reported by the Department of Oral Pathology and Microbiology. Data regarding age, gender, site, and diagnosis were obtained and studied. Results: Amongst the total 5928 biopsied cases reported, 6% were salivary gland pathologies. Two hundred sixty-six were non-neoplastic lesions and 81 were neoplastic. The most common non-neoplastic lesion was mucous extravasation cyst. The most common neoplastic lesion was pleomorphic adenoma. Conclusion: The frequency of occurrence of salivary gland lesions in the last 24 years of this institution is almost similar to that stated in other published studies.

Frequent apocrine changes in pleomorphic adenoma with malignant transformation: a possible pre-malignant step in ductal carcinoma ex pleomorphic adenoma.

BACKGROUND: The most common type of carcinoma ex pleomorphic adenoma (CPA) is histologically equivalent to salivary duct carcinoma, which has an apocrine phenotype. Invasive CPA is often accompanied by non-invasive or in situ carcinoma, an observation that suggests the presence of precursor lesions. The aim of this study was to identify candidate precursor lesions of CPA within pleomorphic adenoma (PA). METHODS: Eleven resected cases of CPA with residual PA and 17 cases of PA with atypical changes were subjected to immunohistochemistry (IHC) for p53, human epidermal growth factor receptor 2 (HER2), androgen receptor (AR), pleomorphic adenoma gene 1, gross cystic disease fluid protein-15 (GCDFP-15), and anti-mitochondrial antibody. RESULTS: Invasive or in situ carcinoma cells in all CPAs were positive for AR, GCDFP-15, and HER2. Atypical foci in PAs corresponded to either apocrine or oncocytic changes on the basis of their reactivity to AR, GCDFP-15, and anti-mitochondrial antibody. Atypical cells in PAs surrounding CPAs had an apocrine phenotype without HER2 expression. CONCLUSIONS: Our study identified frequent apocrine changes in residual PAs in CPA cases, suggesting a possible precursor role of apocrine changes. We recommend the use of HER2 IHC in atypical PAs, and that clinicians take HER2 positivity into serious consideration.

Myoepithelial Carcinoma Ex Pleomorphic Adenoma of the Submandibular Gland: A Case Report.

Carcinoma ex pleomorphic adenoma (Ca-ex-PA) is a rare tumor that arises from the malignant transformation of a primary or recurrent pleomorphic adenoma. Despite being benign, pleomorphic adenomas can rarely undergo malignant transformation. Risk factors include a long-standing primary tumor, a prior history of radiation exposure, increased tumor size, and recurrent disease. Ca-ex-PA usually affects patients between the sixth and eighth decades of life, approximately 10 to 20 years after the development of a pleomorphic adenoma. Patients usually present with the rapid expansion of an already existing mass. We describe a case report of a patient who presented with Ca-ex-PA of the submandibular gland. The patient underwent surgical excision of the affected gland, which was consistent with a widely invasive myoepithelial Ca-ex-PA. The patient underwent postoperative radiation to the neck and the tumor bed. No local or distant recurrence was noted during the one-year follow-up. Due to the rarity of the disease entity and the infrequent location of the tumor, this case presents a particular diagnostic and therapeutic challenge.

Patterns of Lymph Node Metastasis in Parotid Cancer and Implications for Extent of Neck Dissection.

OBJECTIVE: The role and extent of neck dissection in primary parotid cancer are controversial. Herein, we characterize patterns of lymph node metastasis in parotid cancer. STUDY DESIGN: Retrospective analysis. SETTING: National Cancer Database. METHODS: Patients with the 6 most common histologic subtypes of parotid cancer were selected. Primary outcomes were the distribution of positive lymph nodes by level and overall survival assessed by Cox analysis. Secondary outcomes included predictors of extended lymph node involvement (≥3 lymph nodes or Level IV/V involvement), via logistic regression. RESULTS: Six thousand nine hundred seventy-seven patients with acinic cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, carcinoma ex pleomorphic adenoma (CExPA), mucoepidermoid carcinoma, and salivary duct carcinoma (SDC) were included. Among cN0 patients, 8.2% of low-grade tumor patients had occult nodal metastasis versus 30.9% in high-grade tumor patients. Elective neck dissection was not associated with an overall survival benefit (adjusted hazard ratio: 1.10; 0.94-1.30, p = .238). Among cN+ tumors, CExPA (odds ratio [OR]: 1.88, 1.05-3.39, p = .034) and high-grade pathology (OR: 3.03, 1.87-4.93, p < .001) were predictive of having ≥3 pathologic nodes. CExPA (OR: 2.13, 1.22-3.72, p = .008), adenocarcinoma (OR: 1.60, 1.11-2.31, p = .013), SDC (OR: 1.92, 1.17-3.14, p < .01), and high-grade pathology (OR: 3.61, 2.19-5.97, p < .001) were predictive of Level IV/V neck involvement. CONCLUSIONS: In parotid malignancy, nodal metastasis distribution is dependent on histology and grade. High-grade tumors and certain histologies (SDC and adenocarcinoma) had a higher incidence of occult nodes. Comprehensive neck dissection should also be considered for node-positive high-grade tumors, SDC, and adenocarcinoma.

Carcinoma Ex Pleomorphic Adenomas: An Institutional Experience and Literature Review.

OBJECTIVES: To provide an institutional experience with cases diagnosed as carcinoma ex pleomorphic adenoma (CXPA), including the cytologic and histologic findings and clinical follow-up, followed by a comparison to the experience documented in the literature. METHODS: We identified cases of CXPA diagnosed at our institution from 2011 to 2021 and reviewed the cytologic and histologic diagnoses, as well as the treatment and clinical outcomes. Additionally, a literature review of the English literature was performed on CXPAs from 2011 to 2021. RESULTS: Forty-one cases of CXPA were identified, with the majority subclassified as adenocarcinoma, not otherwise specified. Five tumors underwent cytogenetic studies and five underwent molecular studies. To date, 36 patients are alive, 8 of whom experienced locoregional recurrence or distant metastasis. CONCLUSIONS: Our institutional experience was comparable to that reported in the literature. Further studies are required to inquire about the role of molecular profiles of CXPAs in clinical risk assessment.

Carcinoma ex pleomorphic adenoma of the submandibular gland: A retrospective analysis of 86 patients.

OBJECTIVES: To evaluate the prognostic and locoregional metastatic features of carcinoma ex pleomorphic adenoma of submandibular gland (SMG-CXPA) and improve the understanding of this uncommon condition. PATIENTS AND METHODS: We retrospectively reviewed patients who were diagnosed with SMG-CXPA. The survival data of SMG-CXPA patients were statistically analyzed using Cox regression and Kaplan-Meier method. The associations between cervical metastasis and clinicopathological parameters were evaluated using chi-squared test. Additionally, two different histological categories (histological grade and invasiveness) and their combination were evaluated with the Kaplan-Meier method and receiver operating characteristic curves. RESULTS: In total, 86 patients were diagnosed: 38 clinically node-negative, 31 pathologically node-negative, and 17 node-positive patients. Clinical tumor stage and histological grade were two independent prognostic factors for SMG-CXPA. There were significant correlations between sex, tumor size, clinical tumor stage, clinical lymph node stage, histological grade, invasiveness, malignant components, perineural invasion, and no specific criteria exist for the clinical outcome. CONCLUSION: SMG-CXPA is a high-grade malignancy with an unfavorable prognosis. Elective neck dissection should be performed in SMG-CXPA patients with a risk of locoregional metastasis. Histological grade seems to be a more valuable predictor of lymph node involvement than invasiveness.