PTEN Deregulation Mechanisms in Salivary Gland Carcinomas.

Among the tumour suppressor genes that affect critically cell functions and homeostasis, phosphatase and tensin homolog deleted in chromosome 10 (PTEN- gene locus: 10q21) regulates the PI3K/Akt/mTOR signalling pathway. PTEN is deleted, mutated or epigenetically hyper-methylated in a variety of human solid malignancies. Salivary gland carcinomas (SGCs) belong to the head and neck carcinomas (HNCs) super category of solid malignancies. Histo-pathologically, they demonstrate a significant diversity due to a variety of distinct and mixed subtypes. Genetically, they are characterized by a broad spectrum of gene and chromosomal imbalances. Referring specifically to suppressor genes, PTEN deregulation plays a critical role in signaling transduction in the corresponding SGC pre- and malignant epithelia modifying the response rates to potential targeted therapeutic strategies. In the current review, we explored the role of PTEN deregulation mechanisms that are involved in the onset and progression of SGCs.

Impact of Amplified Oncogenes on Salivary Gland Carcinomas.

In normal epithelia, proto-oncogenes regulate critical intra- or intercellular functions, including cell growth and proliferation, apoptosis, and signaling transduction from the cell periphery (extracellular space) to the nucleus mediated by different pathways. Oncogenes are the mutated or amplified forms of the corresponding proto-oncogenes that are crucially involved in cell neoplastic and malignant transformation during carcinogenesis. Salivary gland carcinomas (SGCs) demonstrate a variety of histogenetic types. They are characterized by a broad spectrum of chromosomal and gene alterations. In particular, amplifications in specific genes [human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 4 (HER4), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), Mouse double minute 2 homolog (MDM2), androgen receptor (AR), programmed death (ligand 1 (PD-L1), neurogenic differentiation factor 2 (NEUROD2), phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 protein (PREX1), cyclin-dependent kinase4/6 (CDK4/6), proline-rich acidic protein 1 (PRAP1), kell antigen system (KEL), glutamate receptor subunit epsilon 2 (GRIN2D), Ewing sarcoma RNA-binding protein 1 (EWSR1), MYC proto-oncogene (MYC)] combined or not with chromosomal numerical imbalances (aneuploidy/ polysomy/monosomy) form different genetic signatures affecting the response to monoclonal antibody-based, oncologicaly targeted regimens. Different SGC histotypes demonstrate specific combinations of mutated/amplified genes that modify their clinicohistological features. In the current molecular review, we present the most important amplified oncogenes and their impact on the biological behavior of SGCS.

Mutational Signatures in Salivary Gland Carcinomas.

Salivary gland carcinomas belong to the head and neck carcinoma super category of malignancies. They are characterized by histopathological diversity and comprise a variety of entities and subtypes. Mucoepidermoid, adenoid cystic and salivary duct carcinomas represent the most prominent malignancies. Concerning their corresponding genetic background, a broad spectrum of gene and chromosomal imbalances has been detected. Point mutations and deletions, amplifications and translocations, combined or not with chromosomal aneuploidy/polysomy/monosomy, create a landscape of specific genetic signatures that affect the biological behavior of these tumors and modify response rates to potential targeted therapeutic strategies. In the current molecular review, we focused on the categorization and description of the most important mutational signatures in salivary gland carcinomas.

The effectiveness of intratympanic steroid injection in addition to systemic corticosteroids in the treatment of idiopathic sudden sensorineural hearing loss.

There is a lot of controversy about the efficacy of intratympanic steroid (ITS) therapy in idiopathic sudden sensorineural hearing loss (ISSHL). ITS are reported to have effect on ISSNHL and ITS with additional systemic therapy are also effective. In the primary treatment of ISSHL, achieving the correct diagnosis rapidly is paramount, as early initial treatment greatly increases the chance of hearing recovery. A retrospective study took place from 2010 to 2017 in the 1st ENT Clinic of Athens. Participants were inward patients that were first examined and diagnosed with ISSNHL in the Emergency Department and afterwards admitted in the clinic. In 2014 our Clinic changed the Treating Protocol of ΙSSNHL. We compared the audiological results of the patients treated with the previous protocol (intravenous steroids) with those treated with the new protocol (concurrent intravenous and intratympanic steroids). The main outcome measure was the hearing threshold before treatment and after completion of therapy. We retrieved from the hospital medical records the following demographic and clinical data: sex, age, date of admission, comorbidities, hearing threshold per frequency on admission and on discharge day and time period between onset of symptoms and initial treatment. We concluded that both intratympanic steroids and systemic steroids alone appear equally effective, however the use of both intratympanic and systemic steroids together is likely superior to either used alone. Intratympanic steroids likely offer additional benefit as a secondary/salvage therapy in patients who fail initial systemic steroid therapy.

Anti-EGFR/BRAF-Tyrosine Kinase Inhibitors in Thyroid Carcinoma.

Alterations in significant genes located on chromosome 7 - including epidermal growth factor receptor (EGFR) and also v-Raf murine sarcoma viral oncogene homolog B (BRAF) as a mitogen-activated protein kinase (MAPK)  - combined or not with numerical imbalances of the whole chromosome (aneuploidy-polysomy) are crucial genetic events involved in the development and progression of malignancies. Identification of EGFR/BRAF-dependent specific somatic mutations and other mechanisms of deregulation (i.e., amplification) is critical for applying targeted therapeutic approaches [tyrosine kinase inhibitors (TKIs] or monoclonal antibodies (mAbs). Thyroid carcinoma is a specific pathological entity characterized by a variety of histological sub-types. Follicular thyroid carcinoma (FTC), papillary thyroid carcinoma (PTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC) represent its main sub-types. In the current review, we explore the role of EGFR/BRAF alterations in thyroid carcinoma in conjunction with the corresponding anti-EGFR/BRAF TKI-based novel therapeutic strategies for patients with specific genetic signatures.

APOBEC3B Is Co-Expressed with PKCα/NF-κB in Oral and Oropharyngeal Squamous Cell Carcinomas.

The enzymatic activity of APOBEC3B (A3B) has been implicated as a prime source of mutagenesis in head and neck squamous cell carcinoma (HNSCC). The expression of Protein Kinase C α (PKCα) and Nuclear Factor-κΒ p65 (NF-κΒ p65) has been linked to the activation of the classical and the non-canonical NF-κB signaling pathways, respectively, both of which have been shown to lead to the upregulation of A3B. Accordingly, the aim of the present study was to evaluate the expression of PKCα, NF-κΒ p65 and A3B in non-HPV related oral and oropharyngeal squamous cell carcinomas (SCC), by means of immunohistochemistry and in silico methods. PKCα was expressed in 29/36 (80%) cases of oral and oropharyngeal SCCs, with 25 (69%) cases showing a PKCα+/A3B+ phenotype and only 6/36 (17%) cases showing a PKCα-/A3B+ phenotype. Εxpression of NF-κB p65 was seen in 33/35 (94%) cases of oral and oropharyngeal SCCs, with 30/35 (86%) cases showing an NF-κB p65+/A3B+ phenotype and only 2/35 (6%) cases showing an NF-κB p65-/A3B+ phenotype. In addition, mRNA expression analysis, using the UALCAN database, revealed strong expression of all three genes. These findings indicate that the expression of A3B is associated with PKCα/NF-κB p65 expression and suggest a potential role for the PKC/NF-κB signaling pathway in the development of oral and oropharyngeal cancer.

The Landscape of Single Nucleotide Polymorphisms in Papillary Thyroid Carcinoma.

Thyroid carcinoma represents a leading malignancy among those derived from human endocrine systems. It comprises a variety of different histological subtypes, including mainly papillary carcinoma, follicular carcinoma, anaplastic carcinoma, and medullar carcinoma. A broad spectrum of genetic imbalances, comprising gross chromosomal (polysomy/aneuploidy) and specific gene (mutations, amplifications, deletions) alterations, has been reported. Interestingly, the role of isolated, specific gene polymorphisms, especially of the single nucleotide polymorphism (SNP) type, in thyroid carcinoma is under investigation. SNPs are the most common genetic variations in the genome. The current molecular review focuses on the impact of specific SNPs on the biological behavior of papillary thyroid carcinoma in their carriers.

A Clinical Case of Delayed Posttraumatic Frontal Sinus Cerebrospinal Fluid Leakage Management Via External Surgical Approach.

ABSTRACT: Cerebrospinal fluid rhinorrhea is frequently encountered after a fracture of the skull base. Individual fractures of the posterior wall of the frontal sinus after brain injury are uncommon. The authors present a case of a 33-year-old man with a distant history of skull base injury after a traffic accident, 12 years ago. He presented with intermittent rhinorrhea and reported 2 episodes of bacterial meningitis the last 7 years since the injury. Cerebrospinal fluid leakage was confirmed with ß2-transferrin testing. Computed tomography and magnetic resonance imaging revealed a small defect of the posterior and superior wall of the left frontal sinus and an ipsilateral meningoencephalocele.Finally, there was a communication between intracranial space and frontal sinus that caused meningitis.A coronal incision and frontal craniotomy with preservation of anterior pericranium was performed (frontal sinus cranialization using osteoplastic flap). In order to determine the precise margins of the frontal sinus and allow an accurate anterior table bone osteotomy and complete exposure of the sinus, the authors used a coronal view of skull X-ray. Scissors are then used to cut along the margins of the sinus. An "R" is scratched into the right side of template to record orientation. The template was sterilized and brought onto the surgical field and then placed over the left sinusAn external surgical approach (anterior table bone osteotomy) with the modern technique of osteoplastic flap access was performed. An elevator was used to separate the dura from the posterior table along the entire margin of the defect. Meningoplasty (cauterization of the meningoencephalocele) and closure of the osseous defect was followed. The authors repaired the defect of the posterior wall of the left frontal sinus using a combination of underlay and overlay technique. Femoral fascia from right thigh and fibrin glue were placed in order to cover the leak of the posterior wall of the left frontal sinus, respectively.Patients who present with a short or/ and distant history of traumatic brain injury should be evaluated for complication of a cerebrospinal fluid leak.

ALK Protein Expression Patterns in Squamous Cell Carcinoma of the Oral Cavity.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is characterized by a broad spectrum of genomic imbalances, including gross chromosomal (polysomy/aneuploidy) ones as well as specific gene alterations. Aberrant expression of anaplastic lymphoma kinase (ALK) seems to be a useful molecular marker for discriminating patients based on genetic signatures in a variety of solid malignancies, such as lung carcinoma. Our aim was to analyze ALK protein expression patterns in a series of OSCCs. MATERIALS AND METHODS: Fifty (n=50) OSCC tissue sections were analyzed by implementing an ALK-based immunohistochemistry protocol. Digital image analysis was performed for measuring the corresponding protein expression levels. RESULTS: ALK overexpression was observed in 14/50 (28%) OSCC tissue sections, whereas the rest 36/50 (72%) demonstrated low expression levels. ALK expression was negatively associated with grade (p=0.027) and stage (p=0.0028) of the examined cases. CONCLUSION: Abnormal ALK expression in subsets of patients with OSCC seems to be related to an aggressive phenotype (advanced stage/progressive dedifferentiation). ALK protein overexpression may be used as a significant marker for applying targeted therapeutic regimens.

Impact of Ubiquitination Signaling Pathway Modifications on Oral Carcinoma.

Among intra-cellular homeostasis mechanisms, ubiquitination plays a critical role in protein metabolism regulation by degrading proteins via activating a broad spectrum of ubiquitin chains. In fact, ubiquitination and sumoylation signaling pathways are characterized by increased complexity regarding the molecules and their interactions. The Ubiquitin-Proteasome System (Ub-PS) recognizes and targets a broad spectrum of protein substrates. Ubiquitin conjugation modifies each substrate protein determining its biochemical fate (degradation). A major functional activity of Ub-PS is autophagy mechanism regulation. Interestingly, Ub-PS promotes all stages of bulk autophagy (initiation, execution, and termination). Autophagy is a crucial catabolic process that provides protein degradation and for this reason the interaction with Ub-PS is crucial. Furthermore, ubiquitination controls and regulates specific types of protein targets. Ub-PS is also involved in oxidative cellular stress and DNA damage response. Additionally, the functional role of Ub-PS in ribosome machinery regulation seems to be crucial. Concerning carcinogenesis, Ub-PS is involved in malignant disease development and progression by negatively affecting the corresponding TGF-B-, MEEK/MAPK/ERK-JNK- dependent signaling pathways. In the current review article, we describe the role of Ub-PS biochemical modifications and alterations in oral squamous cell carcinoma (OSCC).

From delta to Omicron: S1-RBD/S2 mutation/deletion equilibrium in SARS-CoV-2 defined variants.

Coronavirus-related Severe Acute Respiratory Syndrome (SARS-CoV) in 2002/2003, Middle-East Respiratory Syndrome (MERS-CoV) in 2012/2013, and especially the current 2019/2021 Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) affected negatively the national health systems' endurance worldwide. SARS-Cov-2 virus belongs to lineage b of beta-CoVs demonstrating a strong phylogenetic similarity with BatCoVRaTG13 type. Spike (S) glycoprotein projections -consisting of two subunits S1/S2- provide a unique crown-like formation (corona) on virion's surface. Concerning their functional role, S1 represents the main receptor-binding domain (RBD), whereas S2 is involved in the virus-cell membrane fusion mechanism. On Nov 26th 2021, WHO designated the new SARS-CoV-2 strain - named Omicron, from letter ''όµÎ¹κρον'' in the Greek alphabet - as a variant of concern (B.1.1529 variant). Potentially this new variant is associated with high transmissibility leading to elevated infectivity and probably increased re-infection rates. Its impact on morbidity/mortality remains under investigation. In the current paper, analyzing and comparing the alterations of SARS-CoV-2 S RNA sequences in the defined variants (Alpha to Omicron), we observed some interesting findings regarding the S1-RBD/S2 mutation/deletion equilibrium that maybe affect and modify its activity.

The Effect of the Premedication with Systemic Corticosteroids and Antibiotics on Inflammation and Intraoperative Bleeding During Sinonasal Endoscopic Surgery for Chronic Rhinosinusitis with Nasal Polyps (CRSwNP).

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease characterized by a variety of inflammatory mechanisms. Extensive genetic analyses have shown that among the molecules that are involved in its genetic base, interleukins (ILs) play a critical role in the development and progression of CRSwNP. ILs, such us IL-4 (5q31.1), IL-5 (5q31.1), IL-13 (5q31.11), and IL-25 (14q11.2) are found to be overexpressed. PURPOSE: Our aim is to investigate, through a systemic review, the effect of the premedication with systemic corticosteroids and antibiotics on inflammation and intraoperative bleeding during sinonasal endoscopic surgery for CRSwNP. MATERIALS AND METHODS: The search period covered January 1979 to February 2021, using the scientific databases PubMed, Scien-ceDirect, Scopus, Cochrane Library και Google Scholar. Search terms were "effect, premedication, systemic corticosteroids, antibiotics, intraoperative, bleeding, inflammation, sinonasal, endoscopic surgery, chronic rhinosinusitis, and nasal polyposis." RESULTS: From an initial 80 titles found in the above medline databases, the evaluations led to the final inclusion of 15 papers. Eighty titles found in the above medline databases. Eleven titles were excluded as they did not include a summary and full text in English language. Sixty-nine titles collected and duplicate references were searched. Twelve titles were excluded due to double reporting. Fifty-seven articles remained for systematic review. Fourty-two articles were excluded after systematic review and correlation with the research field. Fifteen articles were eventually included in the literature review. CONCLUSIONS: The effect of corticosteroids and antibiotics on the size of nasal polyps, nasal symptoms, and systemic markers of inflammation is significant. Each of the above factors acts on different pathogenetic inflammatory mechanisms.The use of perioperative corticosteroids reduces blood loss and operation time and improves the quality of the surgical field. There are no other medications that have been shown to improve the surgical field and outcome. Whether there is an additive effect on systemic corticosteroids on top of nasal corticosteroids is unclear. The european position paper on rhinosinusitis and nasal polyps steering group advises to use (nasal) corticosteroids before endoscopic sinus surgery.However, it should be considered in future studies whether some minor differences are due to differences in the initial doses of corticosteroids or during treatment in the preoperative period. It is worth mentioning that although high doses of corticosteroids are required to control the progression of rhinosinusitis with nasal polyps, the optimal initial dosage and the total duration of the treatment have not yet been standardized in patients with CRSwNP and future studies are required to determine the 2 above parameters (optimal dosage and duration of treatment). There are, therefore, known risks from corticosteroid administration, and clinicians should consider them when evaluating each patient. Each patient should be considered as an individual case with individualized treatment.

A Rare Cause of Peripheral Facial Nerve Palsy: Chondromyxoid Fibroma of the Temporal Bone.

PURPOSE: To report a rather rare entity of facial palsy due to chondromyxoid fibroma. The authors present a case along with clinico-pathological features, management, treatment options and follow-up. METHODS: The authors present a case of a 29-year-old male who suffered from right facial weakness and numbness for a period of 6-months. imaging studies demonstrated a soft, locally invasive tumor, located mainly in the right temporal bone and extended extracranially. RESULTS: A surgical procedure of local excision followed by cross-facial nerve grafting was performed. CONCLUSIONS: Diagnosis should be based on combination of histo-pathologic and radiographic findings, because of its histological similarities to chondrosarcoma.

Retropharyngeal Space Lipomas. A Systematic Review of the Reported Cases in the Literature.

Retropharyngeal space lipomas (RSLs) comprise a group of very uncommon head and neck benign, soft tissue tumors that originally grow in the retropharyngeal space. They can develop as individual tumors or in the context of syndromic lipomatosis. Symptoms usually arise as expanding RSLs exert pressure on adjacent structures, and clinical manifestations are often atypical and overlapping. Given the rarity of this diagnosis, current evidence is scarce, providing a rather fragmented picture. A literature search was conducted in all major medical databases, without time limitations. Tumors were considered RSLs if a benign lipomatous tumor appeared to develop originally in the retropharyngeal space. Cases with syndromic lipomatosis that demonstrated at least one such tumor involving the retropharyngeal space were included. A total of 52 publications concerning 79 eligible cases were found. Two of these cases concerned patients with Multiple Symmetrical Lipomatosis. A male predominance was found (61.5%, n = 48). Dysphagia (65.2%, n = 43) was by far the most common symptom, followed by snoring (37.9%, n = 25), dyspnoea (34.8%, n = 23) and dysphonia (30.3%, n = 20). The most used imaging modality was Computed Tomography (CT) (64.1%, n = 41). Surgery was the treatment in 73 cases (93.6%). The transcervical was the most selected approach (50.7%, n = 37), followed by the transoral approach (38.4%, n = 28). Complete recovery was reported, following treatment, in 60 cases (75.9%). Retropharyngeal space lipomas are benign tumors with a higher prevalence in male patients. Dysphagia is the most common symptom. Imaging is necessary for diagnosis, with CT scanning being usually sufficient as a single modality test. More than half of the patients in the literature are treated via an external approach. Diminishing of symptoms and full postoperative recovery is the most common outcome. Supplementary Information: The online version contains supplementary material available at 10.1007/s12070-021-02962-6.

Topoisomerase IIa protein expression analysis in oral squamous cell carcinoma.

PURPOSE: Topoisomerases represent a super-family of nucleic enzymes involved in the DNA replication, transcription, recombination, and also chromosome topological formation. Topoisomerase II alpha (Topo IIa-gene location 17q21) is a critical gene associated with response to chemotherapeutic agents such as anthracyclines especially in breast adenocarcinoma. Our aim was to investigate the role of aberrant Topo IIa protein expression in oral squamous cell carcinoma (OSCC). METHODS: Fifty formalin-fixed, paraffin-embedded primary OSCCs tissue sections were used. Immunohistochemistry was performed using an anti- Topo IIa antibody. Digital image analysis was implemented for evaluating objectively the protein expression levels on the corresponding stained nuclei. RESULTS: Topo IIa protein overexpression (moderate to high immunostaining intensity values) was observed in 29/50 (58%) tissue cores, whereas low expression rates were detected in the remaining cases (21/50;42%). Topo IIa overall expression was strongly associated with the differentiation grade of the examined tumors (p=0.037) and also with human papillomavirus (HPV) positivity (p=0.029). No other statistical correlations were identified. CONCLUSIONS: Topo IIa overexpression is observed in significant subsets of OSCCs correlated with the grade of differentiation. Additionally, HPV persistent infection is associated with increased Topo IIa protein expression levels. Topo IIa expression analysis should be critical for identifying patients eligible for applying specific chemotherapeutic strategies based on anti-Topo IIa agents.

Targeting EGFR in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) represents a specific, aggressive pathological entity included in the Head and Neck Carcinoma (HNC) family of malignancies. NPC is derived from the nasopharyngeal epithelia expressing a high invasive and metastatic potential affecting negatively patients' prognosis due to poor survival rates. Concerning pathogenetic factors implicated in its rise and progression, Epstein-Barr virus (EBV) latent but persistent infection is considered the main one. Novel therapeutic strategies are based on targeting specific molecules such as epidermal growth factor receptor (EGFR) by applying anti-EGFR monoclonal antibodies (mABs) that block their natural ligands interrupting also aberrant signal transduction to nucleus. Anti-EGFR therapies combined or not with radiotherapy seem to be a very promising tool in handling the corresponding patients with NPC that demonstrate specific genetic signatures. In the current article, we focused on presenting EGFR expression in NPC combined with novel anti-EGFR agents.

Impact of Topoisomerases Complex Deregulation on Head and Neck Carcinoma Genomic Instability.

Head and neck carcinoma (HNC) comprises a variety of pathological entities. Among them, squamous cell carcinoma (SCC) is histo-pathologically prominent. Specific malignancies, such as nasopharyngeal carcinoma (NPC) arise also from the same anatomical region. In all of them, genomic instability (GI) is implicated not only in the early stages of epithelial malignant transformation, but also in the aggressiveness of the corresponding phenotypes. Among the molecules that are frequently deregulated in solid malignancies including HNCs, topoisomerases (Topo) are of increased significance due to their involvement in DNA topological, structural, and functional stability. The main members are Topo I (20q11), Topo II alpha (17q21) and Topo IIb (3p24). In the current article, we describe the mechanisms of Topo I and Topo IIa deregulation leading to GI in a variety of HNCs. Furthermore, novel data regarding the corresponding targeted therapeutic strategies are presented.

Impact of Ribosome Activity on SARS-CoV-2 LNP - Based mRNA Vaccines.

Coronavirus-related Severe Acute Respiratory Syndrome-2 (SARS-CoV-2) initially was detected in Wuhan, Hubei, China. Since early 2021, World Health Organization (WHO) has declared Coronavirus Disease 2019 (COVID-19) a pandemic due to rapidly transformed to a globally massive catastrophic viral infection. In order to confront this emergency situation, many pharmaceutical companies focused on the design and development of efficient vaccines that are considered necessary for providing a level of normalization in totally affected human social-economical activity worldwide. A variety of vaccine types are under development, validation or even some of them have already completed these stages, initially approved as conditional marketing authorisation by Food and Drug Administration (FDA), European Medicines Agency (EMA), and other national health authorities for commercial purposes (in vivo use in general population), accelerating their production and distribution process. Innovative nucleoside-modified viral messenger RNA (v-mRNA)-based vaccines encapsulated within nanoparticles-specifically lipid ones (LNPs)-are now well recognized. Although this is a promising genetic engineering topic in the field of nanopharmacogenomics or targeted nucleic vaccines, there are limited but continuously enriched in vivo data in depth of time regarding their safety, efficacy, and immune response. In the current paper we expand the limited published data in the field of ribosome machinery and SARS-CoV-2 mRNA fragment vaccines interaction by describing their functional specialization and modifications. Additionally, alterations in post-transcriptional/translational molecules and mechanisms that could potentially affect the interaction between target cells and vaccines are also presented. Understanding these mechanisms is a crucial step for the next generation v-mRNA vaccines development.

Impact of K-Ras Over-expression in Laryngeal Squamous Cell Carcinoma.

BACKGROUND/AIM: Oncogene up-regulation combined with suppressor gene down-regulation is a crucial genetic combination that promotes cell neoplastic phenotype and progressively malignant transformation in solid malignancies, including laryngeal squamous cell carcinoma (LSCC). Among oncogenes, the Kirsten ras oncogene homolog (K-Ras) is involved in LSCC onset and progression. PATIENTS AND METHODS: Sixty (n=60) primary LSCC tissue sections were analyzed by immunohistochemistry (IHC). Digital image analysis (DIA) was also implemented for measuring K-Ras protein expression levels. RESULTS: High K-Ras protein expression levels were observed in 20/60 (33.3%) LSCC tissue sections, whereas the rest of the cases (n=40; 66.7%) demonstrated low expression. Overall K-Ras expression was borderline significantly associated to the grade of the examined malignancies (p=0.048), whereas no other strong statistical correlations were identified. A progressive K-Ras overexpression was observed in all grades of the examined cases. CONCLUSION: K-Ras over expression is correlated to a progressive dedifferentiation in LSCC.

Primary Large Cell Neuroendocrine Carcinoma of the Parotid Gland. Report of a Rare Case.

Primary neuroendocrine carcinomas of the salivary glands are very rare neoplasms that present light microscopic, ultrastructural, and immunohistochemical features of neuroendocrine differentiation. Twelve cases have been published in the English language literature. We describe the pathologic features of a case of primary large cell neuroendocrine carcinoma of the parotid gland in a 91-year old male and summarize the immunophenotype of previously reported LCNECs of the major salivary glands. It is concluded that primary LCNEC of the salivary glands presents as a high-grade undifferentiated carcinoma, whose diagnosis may be hindered by its rarity and non-specific light microscopic features. A high level of awareness, immunohistochemical staining for neuroendocrine markers synaptophysin and CD56, and a thorough diagnostic work-up in order to exclude metastasis from a primary neuroendocrine carcinoma will allow its diagnosis.