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, 2023.

[1]  Fei Liu,et al.  Head and Neck Cancer Immunotherapy: Molecular Biological Aspects of Preclinical and Clinical Research , 2023, Cancers.

[2]  Hyojin Kim,et al.  Identification of differentially expressed microRNAs as potential biomarkers for carcinoma ex pleomorphic adenoma , 2022, Scientific Reports.

[3]  Tao Zhang,et al.  Prognostic role of PD-L1 expression in patients with salivary gland carcinoma: A systematic review and meta-analysis , 2022, PloS one.

[4]  M. García-Cosío,et al.  Recommendations for the use of biomarkers for head and neck cancer, including salivary gland tumours: a consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology , 2022, Clinical and Translational Oncology.

[5]  M. Shakweer,et al.  Immunohistochemical Study of Cancer Stem Cell marker, Tight Junction Protein, and Lymphatic Density in Malignant Salivary Gland Tumors , 2022, Open Access Macedonian Journal of Medical Sciences.

[6]  C. Antonescu,et al.  Targeted RNA sequencing in the routine clinical detection of fusion genes in salivary gland tumors , 2021, Genes, chromosomes & cancer.

[7]  C. Kristensen,et al.  HER2 Positivity in Histological Subtypes of Salivary Gland Carcinoma: A Systematic Review and Meta-Analysis , 2021, Frontiers in Oncology.

[8]  S. Ergün,et al.  2021 Update on Diagnostic Markers and Translocation in Salivary Gland Tumors , 2021, International journal of molecular sciences.

[9]  Siyi Li,et al.  Carcinoma ex pleomorphic adenoma of major salivary glands: CT and MR imaging findings. , 2021, Dento maxillo facial radiology.

[10]  M. Wierzbicka,et al.  Expression of p16Ink4a protein in pleomorphic adenoma and carcinoma ex pleomorphic adenoma proves diversity of tumour biology and predicts clinical course , 2021, Journal of Clinical Pathology.

[11]  Nofisat Ismaila,et al.  Management of Salivary Gland Malignancy: ASCO Guideline , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  N. Rupp,et al.  SalvGlandDx – a comprehensive salivary gland neoplasm specific next generation sequencing panel to facilitate diagnosis and identify therapeutic targets , 2021, Neoplasia.

[13]  Sameer Allahabadi,et al.  Genomic Analysis of Salivary Gland Cancer and Treatment of Salivary Gland Cancers. , 2021, Surgical pathology clinics.

[14]  Y. Matsuno,et al.  Enhanced Angiogenesis in Salivary Duct Carcinoma Ex-Pleomorphic Adenoma , 2021, Frontiers in Oncology.

[15]  A. Leme,et al.  Prognostic value of the immunohistochemical expression of vascular endothelial growth factors in malignant salivary gland neoplasms: a systematic review and meta-analysis , 2021, Medicina oral, patologia oral y cirugia bucal.

[16]  S. Sarıoğlu,et al.  Molecular Pathology of Salivary Gland Neoplasms: Diagnostic, Prognostic, and Predictive Perspective. , 2021, Advances in anatomic pathology.

[17]  K. Tsukinoki,et al.  The significance of tyrosine kinase receptor B and brain-derived neurotrophic factor expression in salivary duct carcinoma. , 2020, Annals of diagnostic pathology.

[18]  E. Mayo-Wilson,et al.  PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews , 2020, BMJ.

[19]  J. Klijanienko,et al.  Salivary gland cancer in the era of immunotherapy: can we exploit tumor microenvironment? , 2020, Expert opinion on therapeutic targets.

[20]  S. Ghanaati,et al.  Prognostic impact of CD8-positive tumour-infiltrating lymphocytes and PD-L1 expression in salivary gland cancer. , 2020, Oral oncology.

[21]  A. Quaas,et al.  Lymphocyte activation gene 3 (LAG3) protein expression on tumor-infiltrating lymphocytes in aggressive and TP53-mutated salivary gland carcinomas , 2020, Cancer Immunology, Immunotherapy.

[22]  Y. Hirose,et al.  Programmed death ligand-1 expression is associated with stage and histological grade of parotid carcinoma , 2020, Acta oto-laryngologica.

[23]  S. Dogan,et al.  Androgen receptor immunohistochemistry in salivary duct carcinoma: a retrospective study of 188 cases focusing on Tumoral heterogeneity and temporal concordance. , 2019, Human pathology.

[24]  P. Grossmann,et al.  Biomarker Immunoprofile and molecular characteristics in salivary duct carcinoma: Clinicopathologic and prognostic implications. , 2019, Human pathology.

[25]  P. Stafford,et al.  Novel therapeutic targets in salivary duct carcinoma uncovered by comprehensive molecular profiling , 2019, Cancer medicine.

[26]  H. Moch,et al.  The expression of PD-L1 in salivary gland carcinomas , 2019, Scientific Reports.

[27]  P. Golusiński,et al.  Prognostic markers in salivary gland cancer and their impact on survival , 2019, Head & neck.

[28]  V. C. de Araújo,et al.  Estrogen Receptor, Progesterone Receptor, and HER-2 Expression in Recurrent Pleomorphic Adenoma , 2019, Clinical pathology.

[29]  S. Nguyen,et al.  Carcinoma ex pleomorphic adenoma: A review of incidence, demographics, risk factors, and survival. , 2019, American journal of otolaryngology.

[30]  M. Berger,et al.  The repertoire of genetic alterations in salivary duct carcinoma including a novel HNRNPH3-ALK rearrangement. , 2019, Human pathology.

[31]  Tsuyoshi Saito,et al.  Clinicopathological effect of PLAG1 fusion genes in pleomorphic adenoma and carcinoma ex pleomorphic adenoma with special emphasis on histological features , 2018, Histopathology.

[32]  J. Krane,et al.  Ancillary testing in salivary gland cytology: A practical guide , 2018, Cancer cytopathology.

[33]  N. Cipriani,et al.  Expression of Hormone Receptors and HER-2 in Benign and Malignant Salivary Gland Tumors , 2018, Head and Neck Pathology.

[34]  C. Antonescu,et al.  PLAG1 immunohistochemistry is a sensitive marker for pleomorphic adenoma: a comparative study with PLAG1 genetic abnormalities , 2018, Histopathology.

[35]  Simion I. Chiosea,et al.  HMGA2 is a specific immunohistochemical marker for pleomorphic adenoma and carcinoma ex‐pleomorphic adenoma , 2017, Histopathology.

[36]  V. Alves,et al.  Increased SOX2 expression in salivary gland carcinoma ex pleomorphic adenoma progression: an association with adverse outcome , 2017, Virchows Archiv.

[37]  Yang Gao,et al.  Absence of myoepithelial cells correlates with invasion and metastasis of Carcinoma ex pleomorphic adenoma. , 2017, International journal of oral and maxillofacial surgery.

[38]  S. Fujii,et al.  Concomitant expression of ezrin and HER2 predicts distant metastasis and poor prognosis of patients with salivary gland carcinomas. , 2017, Human pathology.

[39]  M. Mollenhauer,et al.  Histological, immunohistological and molecular characteristics of intraductal precursor of carcinoma ex pleomorphic adenoma support a multistep carcinogenic process , 2017, Virchows Archiv.

[40]  Jiang Li,et al.  A low percentage of HER‐2 amplification whereas indicates poor prognosis in salivary carcinoma ex pleomorphic adenoma: a study of 140 cases , 2017, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[41]  R. Seethala,et al.  Update from the 4th Edition of the World Health Organization Classification of Head and Neck Tumours: Tumors of the Salivary Gland , 2017, Head and Neck Pathology.

[42]  L. Kowalski,et al.  Loss of expression of Plag1 in malignant transformation from pleomorphic adenoma to carcinoma ex pleomorphic adenoma. , 2016, Human pathology.

[43]  Simion I. Chiosea,et al.  Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations , 2016, Cancer.

[44]  G. Frampton,et al.  Comprehensive genomic profiles of metastatic and relapsed salivary gland carcinomas are associated with tumor type and reveal new routes to targeted therapies , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[45]  M. Odenthal,et al.  MDM2 and CDK4 amplifications are rare events in salivary duct carcinomas , 2016, Oncotarget.

[46]  S. Fukuda,et al.  Carcinoma ex pleomorphic adenoma of the parotid gland: a multi-institutional retrospective analysis in the Northern Japan Head and Neck Cancer Society , 2016, Acta oto-laryngologica.

[47]  G. Stenman,et al.  The landscape of gene fusions and somatic mutations in salivary gland neoplasms - Implications for diagnosis and therapy. , 2016, Oral oncology.

[48]  P. Speight,et al.  Molecular signature of salivary gland tumors: potential use as diagnostic and prognostic marker. , 2016, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[49]  N. Nikolic,et al.  High frequency of p16 and p14 promoter hypermethylation and marked telomere instability in salivary gland tumors. , 2015, Archives of oral biology.

[50]  T. Nakano,et al.  Dual gain of HER2 and EGFR gene copy numbers impacts the prognosis of carcinoma ex pleomorphic adenoma. , 2015, Human pathology.

[51]  C. Tufanaru,et al.  Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data , 2015, International journal of evidence-based healthcare.

[52]  M. Aerts,et al.  Metaprop: a Stata command to perform meta-analysis of binomial data , 2014, Archives of Public Health.

[53]  K. Baroudi,et al.  Immunohistochemical expression of p16 in Carcinoma Ex-pleomorphic Adenoma (undifferentiated and Adenocarcinoma Types). , 2013, Journal of clinical and diagnostic research : JCDR.

[54]  C. Bombardier,et al.  Assessing Bias in Studies of Prognostic Factors , 2013, Annals of Internal Medicine.

[55]  S. Komune,et al.  HER‐2/neu gene amplification in carcinoma ex pleomorphic adenoma in relation to progression and prognosis: a chromogenic in‐situ hybridization study , 2012, Histopathology.

[56]  Robert A. Smith,et al.  Carcinoma ex Pleomorphic Adenoma: A Comprehensive Review of Clinical, Pathological and Molecular Data , 2012, Head and Neck Pathology.

[57]  J. Roh,et al.  Carcinoma ex Pleomorphic Adenoma of the Salivary Glands: Distinct Clinicopathologic Features and Immunoprofiles Between Subgroups According to Cellular Differentiation , 2011, Journal of Korean medical science.

[58]  Jiang Li,et al.  Aberrant protein expression and promoter methylation of p16 gene are correlated with malignant transformation of salivary pleomorphic adenoma. , 2011, Archives of pathology & laboratory medicine.

[59]  O. Kujan,et al.  Immunohistochemical Expression of p53 in Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma , 2010, Journal of cancer epidemiology.

[60]  C. Furuse,et al.  Study of growth factors and receptors in carcinoma ex pleomorphic adenoma. , 2010, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[61]  P. Sloan,et al.  Immunohistochemical expression of estrogens and progesterone receptors in carcinoma ex pleomorphic adenoma-undifferentiated and adenocarcinoma types. , 2010, Medicina oral, patologia oral y cirugia bucal.

[62]  B. Erovic,et al.  Transformation of pleomorphic adenoma to carcinoma ex pleomorphic adenoma of the parotid gland is independent of p53 mutations , 2010, Journal of surgical oncology.

[63]  Y. Okamoto,et al.  Expressions of androgen receptor and its co‐regulators in carcinoma ex pleomorphic adenoma of salivary gland , 2009, Pathology.

[64]  H. Kosmehl,et al.  KRAS status and epidermal growth factor receptor expression as determinants for anti-EGFR therapies in salivary gland carcinomas. , 2009, Oral oncology.

[65]  T. Ettl,et al.  Overexpression of EGFR and absence of C‐KIT expression correlate with poor prognosis in salivary gland carcinomas , 2008, Histopathology.

[66]  V. Alves,et al.  Desmoplasia in Different Degrees of Invasion of Carcinoma Ex-Pleomorphic Adenoma , 2007, Head and neck pathology.

[67]  T. Yoshihara,et al.  Carcinoma ex pleomorphic adenoma of the salivary gland: an immunohistochemical study , 2007, European Archives of Oto-Rhino-Laryngology.

[68]  M. Tsukuda,et al.  Expression of epidermal growth factor receptor, transforming growth factor-α and Ki-67 in relationship to malignant transformation of pleomorphic adenoma , 2007, Acta oto-laryngologica.

[69]  H. Gobbi,et al.  Immunohistochemical expression of p63 in pleomorphic adenomas and carcinomas ex-pleomorphic adenomas of salivary glands. , 2006, Oral oncology.

[70]  I. Leivo,et al.  Non‐invasive (intracapsular) carcinoma ex pleomorphic adenoma: recognition of focal carcinoma by HER‐2/neu and MIB1 immunohistochemistry , 2005, Histopathology.

[71]  W. Xin,et al.  Prognostic factors in malignant mixed tumors of the salivary gland: correlation of immunohistochemical markers with histologic classification. , 2002, Annals of diagnostic pathology.

[72]  J. Klijanienko,et al.  Fine‐needle sampling findings in 26 carcinoma ex pleomorphic adenomas: Diagnostic pitfalls and clinical considerations , 1999, Diagnostic cytopathology.

[73]  K. Sasaki,et al.  Detection of numeric abnormalities of chromosome 17 and p53 deletions by fluorescence in situ hybridization in pleomorphic adenomas and carcinomas in pleomorphic adenoma , 1997, Cancer.

[74]  S. Syrjänen,et al.  Expression and mutations of p53 in salivary gland tumours. , 1997, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[75]  A. Félix,et al.  p53 Immunoexpression in Carcinomas Arising in Pleomorphic Adenoma , 1996 .

[76]  T. Gansler,et al.  c-erbB-2 oncoprotein expression and amplification in pleomorphic adenoma and carcinoma ex pleomorphic adenoma: relationship to prognosis. , 1994, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[77]  V. Kataja,et al.  c-erbB-2 oncogene expression in salivary gland tumours. , 1994, ORL; journal for oto-rhino-laryngology and its related specialties.

[78]  Y. Hayashi,et al.  c‐myc, ras p21 and p53 Expression in pleomorphic adenoma and its malignant form of the human salivary glands , 1993, Acta pathologica japonica.

[79]  OUP accepted manuscript , 2022, Japanese Journal Of Clinical Oncology.

[80]  Yan Gao,et al.  Carcinoma Ex Pleomorphic Adenoma: Is It a High-Grade Malignancy? , 2016, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.