Insights into the molecular alterations of PLAG1 and HMGA2 in the malignant phenotype acquisition in pleomorphic adenoma.

Pleomorphic adenoma (PA) is the most common neoplasm of the salivary gland, presenting with a variety of histological features. In some cases, PA can undergo malignant transformation to carcinoma ex pleomorphic adenoma (CXPA). The transition from PA to CXPA is associated with complex molecular alterations, particularly involving the pleomorphic adenoma gene 1 (PLAG1) and high mobility group protein gene (HMGA2). This review investigates the molecular alterations of PLAG1 and HMGA2 in all domains in the malignant transformation of PA. Our analysis highlights that these markers are key alterations in the etiopathogenesis of PA and CXPA, with gene fusion and amplification being frequently reported mechanisms. Although the exact role of PLAG1 and HMGA2 in the oncogenic process remains unclear, further studies on the HMGA2 and PLAG1, are needed particularly in HMGA2-PLAG1-IGF2 which is proving to be a potential pathway for the development of clinically applicable therapies, especially for CXPA management.

Expanding the Molecular Spectrum of Carcinoma Ex Pleomorphic Adenoma: An Analysis of 84 Cases With a Novel HMGA2::LINC02389 Fusion.

Carcinoma ex pleomorphic adenoma (CXPA) is an aggressive epithelial and/or myoepithelial neoplasm that arises in association with a pleomorphic adenoma (PA). Its etiopathogenesis remains poorly understood, but it is believed that the development of this tumor is due to the accumulation of genetic, protein, metabolic, and epigenetic alterations in a PA. A retrospective review of the Salivary Gland Tumor Registry in Pilsen yielded 84 CXPA, namely 25/84 salivary duct carcinoma (SDC), 15/84 myoepithelial carcinoma (MC), 1/84 epithelial-myoepithelial carcinoma (EMC), and 1/84 adenoid cystic carcinoma (AdCC). All 84 CXPA cases were analyzed by next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH). Forty-three tumors originally diagnosed as CXPA (43/84, 51.2%) showed some molecular alteration. Fusion transcripts were identified in 12/16 (75%) CXPA, including LIFR::PLAG1, CTNNB1::PLAG1, FGFR1::PLAG1, and a novel fusion, HMGA2::LINC02389. Most of the fusions were confirmed by FISH using PLAG1 (6/11) and HMGA2 (1/1) gene break probes. Split signals indicating gene break were identified by FISH for PLAG1 (12/17), HMGA2 (3/4), EWSR1 (7/22), and MYB (2/7). Concerning pathogenic mutations, only CXPA with epithelial differentiation (SDC) presented these alterations, including HRAS mutation (2/4), TP53 (1/4), PTEN (1/4), and ATK1 (1/4). In addition, amplifications in ERBB2 (17/35), MDM2 (1/4), and EWSR1 (1/7) were detected. A novel finding was the discovery of an HMGA2::LINC02389 fusion in 1 patient with EMC ex-PA. The present results indicate that molecular profiling of CXPA with myoepithelial differentiation (MC) tends to reveal chromosomal fusion events, whereas CXPA with epithelial differentiation (SDC) tends to have a higher frequency of pathogenic mutations and gene amplifications.

Secretory carcinoma of the minor salivary gland: An in-depth case report.

A 56-year-old female was referred to our service for management of a malignant salivary gland neoplasm with compromised margins that had been biopsied previously at another service. The patient reported a twenty-year history of a lesion in the oral cavity with progressive and exuberant growth over the past two years, associated with local pain and dyspnea. Physical examination revealed an erythematous, ulcerated, and hemorrhagic lesion measuring approximately 3 cm on the left soft palate and tonsillar pillar. Computed tomography revealed an expansile lesion in the topography of the left soft palate, growing predominantly toward the lumen of the nasopharynx and partially invading the left wall of this region. The patient underwent surgery and histopathologic examination revealed an infiltrative and aggressive epithelial neoplasia with large vacuolated and eosinophilic cytoplasm, vesicular nuclei, and prominent nucleoli. The neoplastic cells were arranged in a solid, microcystic, tubular, and follicular pattern with eosinophilic luminal secretion. Mitotic figures were frequent and all margins were affected by the neoplasia. Morphologic and immunohistochemical features supported the diagnosis of secretory carcinoma, and the patient is currently being followed for further therapeutic intervention.

Solitary Angiokeratoma in the Oral Cavity: A Critical Literature Review and Report of a New Case.

This study aimed to perform an integrative review of solitary angiokeratomas cases in the oral cavity and to report a new case in a 39-year-old man. A modified PECOS strategy was used using PubMed, Embase, Scopus, Web of Science databases, and the reference lists of the selected articles. Case reports of oral solitary angiokeratoma published in English, Portuguese, and Spanish languages with histopathological diagnosis without the presence of systemic disorders were included. Of the 51 articles identified, 18 met the eligibility criteria. Solitary angiokeratomas have a slight male predilection, with a peak incidence in the fourth decade of life. The tongue was the most common localization (77.7%), followed by buccal mucosa (11.1%), labial mucosa (5.6%), and tonsillar pillar (5.6%). The granulomatous appearance was the most frequent clinical aspect. Surgical excision was implemented in 94.4% of the cases. The lesion presented a good prognosis, with no recurrence in 3 to 24 months. In summary, solitary angiokeratoma is a rare lesion in the oral cavity. The professional making the oral diagnosis should be familiar with the clinical manifestation of angiokeratoma and be prepared to consider it in the differential diagnosis of pigmented lesions since these lesions may be part of systemic disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-024-04631-w.

Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets.

The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. In colorectal cancer (CRC), it is involved in different processes including tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. However, conflicting data regarding Eph receptors in CRC, especially in its putative role as an oncogene or a suppressor gene, make the precise role of Eph-ephrin interaction confusing in CRC development. In this review, we provide an overview of the literature and highlight evidence that collaborates with these ambiguous roles of the Eph/ephrin system in CRC, as well as the molecular findings that represent promising therapeutic targets.

Dynamic Role of miRNAs in Salivary Gland Carcinomas: From Biomarkers to Therapeutic Targets.

BACKGROUND: Salivary gland carcinomas (SGCs) are a rare group of malignant neoplasms of the head and neck region. MicroRNAs (miRNAs) are a class of small non-coding RNAs that have been associated with the control biological process and oncogenic mechanism by the regulation of gene expression at the post-transcriptional level. Recent evidence has suggested that miRNA expression may play a role in the tumorigenesis and carcinogenesis process in SGCs. METHODS: This review provides a comprehensive literature review of the role of miRNAs expression in SGCs focusing on the diagnostic, prognostic, and therapeutic applications. RESULTS: In this review, numerous dysregulated miRNAs have demonstrated an oncogenic and suppressor role in SGCs. CONCLUSION: In the future, these miRNAs may eventually constitute useful diagnostic and prognostic biomarkers that may lead to a better understanding of SGCs oncogenesis. Additionally, the development of therapeutic agents based on miRNAs may be a promising target in SGC treatment.

Reported physical examination methods for screening of oral cancer and oral potentially malignant disorders: a systematic review.

OBJECTIVE: This systematic review aimed to describe the method followed during physical examination and the anatomical structures of the head and neck assessed in screening for oral cancer and oral potentially malignant disorders (OPMDs). STUDY DESIGN: An extensive literature search was carried out using MEDLINE/PubMed, EMBASE, Scopus, LILACS, Web of Science, Cochrane databases, and gray literature. The risk of bias was available in all papers included. RESULTS: Of 9,688 records identified, 27 were included in this review, reporting data from 356,250 individuals screened and distributed across 11 countries. Most of these (n = 19) were based on 1 round of screening conducted by a dental professional or other health care workers. Most screening programs included visual inspection and palpation of the lips, oral cavity, and the most visible oropharyngeal sites, but the descriptions reported were imprecise. Additional inspection and palpation of the neck (submental, submandibular, cervical, and supraclavicular regions) to assess for the presence of swellings and any palpable neck nodes were also performed in 15 programs. CONCLUSION: In conclusion, there was considerable heterogeneity in the method of physical examination in screening programs for oral cancer and OPMDs among the included studies.

Clinical and epidemiological profile of burning mouth syndrome patients following the International Headache Society classification: a systematic review and meta-analysis.

OBJECTIVE: This systematic review aimed to determine the clinical and epidemiologic profile of patients with burning mouth syndrome (BMS) following the current classification of the International Headache Society (IHS)-the International Classification of Headache Disorders (ICHD-3) and the International Classification of Orofacial Pain (ICOP). STUDY DESIGN: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and involved a comprehensive search on PubMed, Scopus, EMBASE, Web of Science, LILACS, and the gray literature. RESULTS: Of the 4,252 studies identified, 41 were included. In general, there were no differences between the clinical and epidemiologic profiles of patients with BMS classified based on ICHD-3 or ICOP. Studies were pooled in meta-analyses and showed a significant prevalence of female patients between the sixth and seventh decade of life. The burning sensation and the tongue were the most prevalent descriptors and affected location. Significant associations were demonstrated between BMS and anxiety (P = .0006), depression (P = .004), and poor oral hygiene (P = .00001). CONCLUSIONS: Under the existing contemporary classification systems, patients with BMS were found to be mostly females in the sixth and seventh decade of life with a burning sensation on the tongue. Experiencing depression and anxiety was a commonly existing comorbidity.

Hematopoietic colony-stimulating factors in head and neck cancers: Recent advances and therapeutic challenges.

Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy.

Clinicopathological profile of sclerosing polycystic adenoma/adenosis: A systematic review.

In this systematic review, we aimed to evaluate the clinicopathological profile of sclerosing polycystic adenoma (SPA). PubMed, Scopus, EMBASE, Lilacs, Web of Science, and gray literature were searched to access cases of SPA in salivary glands. One hundred and thirty cases of SPA were found across 61 selected articles. SPA affected mainly the parotid gland of adults with a mean age of 44.6 years old, with a slight preference for females. The lesion was usually presented as a painless firm mass with a long period of evolution. Histologically, they are well-delimitated lesions composed of acinar and ductal elements with a variety of cytomorphologic features surrounded by a densely collagenized stroma. PI3K was the most common gene mutation related to SPA. SPA is a benign condition that mainly affects the parotid gland of female patients and it is usually treated by surgical resection with a good prognosis.

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.

Discovery proteomics reveals potential protein signature associated with malignant phenotype acquisition in pleomorphic adenoma.

OBJECTIVE: To analyze the proteomic profile of salivary pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (CXPA) samples and correlate them with the malignant transformation of the PA. MATERIALS AND METHODS: Thirty samples (10 PA, 16 CXPA, and 4 residual PA) were microdissected and submitted to liquid chromatography-tandem mass spectrometry (LC-MS/MS). The proteomic data and protein identification were analyzed through LC-MS/MS spectra using the MaxQuant software. RESULTS: The proteomic analysis identified and quantified a total of 240 proteins in which 135 were found in PA, residual PA, and CXPA. The shared proteins were divided into six subgroups, and the proteins that showed statistically significant differences (p > 0.05) and fold-change > or <2.5 in one subgroup to another subgroup were included. Seven proteins (Apolipoprotein A-I-APOA1, haptoglobin-HP, protein of the synaptonemal complex 1-SYCP1, anion transport protein of band 3-SLC4A1, subunit µ1 of AP-1 complex-AP1M1, beta subunit of hemoglobin-HBB, and dermcidin-DCD) were classified as potential protein signatures, being HP, AP1M1, and HBB with higher abundance for PA to residual PA, APOA1 with higher abundance for PA to CXPA, SLC4A1 with lower abundance in the PA to CXPA, SYCP1with lower abundance for residual PA to CXPA, and DCD with higher abundance in the CXPA with epithelial differentiation to myoepithelial differentiation. CONCLUSIONS: In this work, we demonstrated the comparative proteomic profiling of PA, residual PA, and CXPA, and seven were proposed as protein signatures, some of which may be associated with the malignant phenotype acquisition.

Oral Teratoma with Hairy Polyp-Like Features: A Brief Report of a Rare Presentation.

We present a 21-day-old female child presenting with a large oral epithelialized tumor implanted at the rhinopharynx and ethmoid plate through a cleft palate, associated with feeding and respiratory difficulties. The histopathological exam showed mature central adipose tissue, hair follicles, sebaceous glands, and neurovascular structures, lined by keratinized stratified squamous epithelium. Proliferative cartilaginous, glandular, lymphatic, bony, and immature myxoid tissue was seen at the posterior region and insertion. Despite the characterization of the tumor as a teratoma containing structures derived from the three embryonic leaflets, the anterior portion presented a microscopic bigeminal pattern fully compatible with hairy polyp.

Clinicopathological and survival profile of patients with salivary gland myoepithelial carcinoma: A systematic review.

OBJECTIVES: In this systematic review, we aimed to evaluate the clinicopathological and prognosis data of patients with salivary gland myoepithelial carcinoma. MATERIALS AND METHODS: MEDLINE/PubMed, Scopus, and Embase search was performed with the keywords "myoepithelial carcinoma" "malignant myoepithelioma," and "salivary glands." Primary salivary glands myoepithelial carcinoma that fulfilled the World Health Organization diagnostic criteria were included. The Joanna Briggs Institute tool was used to assess the risk of bias. RESULTS: Forty-three studies (71 patients) met the inclusion criteria. The patients showed a mean age of 56.4 ± 19.6 years with no sex predilection. The parotid was the most affected gland (49.3%). The tumor presented as an asymptomatic (65.1%) mass (84%). The most common histological findings were the presence of clear tumor cells (39.7%) and multinodular growth patterns (60.7%). Multivariate analysis showed plasmacytoid cell type (p = 0.010) and solid growth pattern (p = 0.003) were related to decreased disease-free survival. Surgery alone was the most used treatment (53.5%). Patients with a combination of treatments showed a longer disease-free survival (p = 0.049). The 2-year and 5-year overall survival rates were 67.5% and 46.1%, respectively. CONCLUSION: Salivary gland myoepithelial carcinoma showed no sex predilection, with a higher incidence in the parotid gland. Cell type, growth pattern, and treatment type may be related to a lower disease-free survival. Overall, salivary gland myoepithelial carcinoma presented low recurrence and metastasis rates. Registration and protocol: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022311512).

Immunopathological insights into villitis of unknown etiology on the basis of transplant immunology.

Villitis of unknown etiology (VUE) is an inflammatory disease characterized by the infiltration of maternal CD8 +T cells into the placental villi. Although the pathogenesis of VUE is still debated, dysregulation of the immune system appears to be an important factor in the development of the disease. Interaction of maternal T cells with the fetal antigens seems to be the trigger for the VUE onset. In this context, graft vs host disease (GVHD) and allographic rejection seem to share similarities in the VUE immunopathological mechanism, especially those related to immunoregulation. In this review, we compared the immunological characteristics of VUE with allograft rejection, and GVHD favoring a better knowledge of VUE pathogenesis that may contribute to VUE therapeutics strategies in the future.

Head and neck squamous cell carcinoma: Exploring frontiers of combinatorial approaches with tyrosine kinase inhibitors and immune checkpoint therapy.

Squamous cell carcinomas (SCC) are the most common malignant tumors that arise in the head and neck. Despite advances in the management of affected patients, the mortality burden of these tumors is increasing every year. The discovery of a vast genetic landscape has revealed new opportunities for therapeutic intervention of head and neck SCC (HNSCC). Molecular alterations of tyrosine kinases are involved in the pathogenesis of cancer and may help keep cancer cells from growing. Currently, many drugs inhibit this enzyme family and are being studied by the pharmaceutical industry opening the room to expand the use and efficacy of this therapeutic modality alone or using combinatorial approaches including checkpoint inhibitors for treatment. In this paper, we explored the role of tyrosine kinases inhibitors of HNSCC, and clinical trials related to these molecules, expecting to provide references for HNSCC therapy.

Tumor microenvironment in salivary gland carcinomas: An orchestrated state of chaos.

Salivary gland carcinomas (SGC) are rare tumors of heterogeneous morphology and many histological subtypes. Like other tumors, the SGC mass consists of a varied population of malignant cells and a diverse array of immune cells, cancer-associated fibroblasts, cytokines, chemokines, extracellular matrix proteins, and metalloproteinases, collectively known as the tumor microenvironment (TME). This chaotic network serves as an important physical mediator of cancer cell growth. In this review, we provided current insights into the TME of some of the most common SGC. Here, we highlighted the histological heterogeneity of these tumors, delineated the nature/intensity of inflammatory infiltrates, and the mechanisms involved in immunological escaping related to each SGC subtype.