Field cancerization is a fundamental paradigm in tumorigenesis, emphasizing that carcinogenesis begins long before the appearance of clinically detectable lesions and often precedes recognizable premalignant changes. A direct manifestation of this process is the molecular dysregulation observed in the peritumoral mucosa-histologically normal-appearing tissue that nonetheless exhibits genetic and epigenetic alterations similar to those of the adjacent tumor. This review summarizes current evidence on the molecular alterations shared between tumor tissue and peritumoral mucosa in HNSCC and evaluates their potential as biomarkers for defining molecular margins and improving surgical precision. A literature search was conducted in PubMed using combinations of the keywords "peritumor," "laryngeal", "HNSCC," and "field cancerization." Studies were included if they directly compared tumor tissue with peritumoral mucosa and, preferably, a third set of distant normal control samples. Only nine studies met the inclusion criteria, highlighting the scarcity of focused research in this area. Reported biomarkers exhibiting comparable dysregulation in both tumor and peritumor tissues include MDM2, E2F2, CDKN2A/p16, ETS-1, MGMT, and multiple microRNAs (e.g., miR-21, miR-96-5p, miR-145-5p). These molecular signatures demonstrate the presence of a biologically altered field extending beyond histologically defined tumor margins. Peritumoral mucosal dysregulation, as a consequence of field cancerization, underscores the need to redefine surgical margins at the molecular level. The identification and validation of biomarkers reflecting this continuum could enable the establishment of molecular margins-improving risk assessment, reducing local recurrence, and advancing personalized oncologic surgery in HNSCC. Standardizing definitions and sampling protocols for "normal adjacent tissue" remains essential for future translational research.

BACKGROUND:MicroRNAs play a critical role in laryngeal carcinogenesis, yet their stage-dependent dysregulation in tumor and peritumoral mucosa remains unclear. OBJECTIVES:To evaluate expression of miR-144 and miR-145 in tumor and peritumoral mucosa of early- and advanced-stage laryngeal carcinoma, and assess their association with stage progression and field cancerization. METHODS:Expression levels of miR-144 and miR-145 were analyzed by qPCR in tumor and matched peritumoral mucosa from 91 patients (26 early-stage glottic and 60 advanced-stage laryngeal carcinomas). RESULTS:In early-stage tumors, miR-144 was downregulated in 32% and miR-145 in 36% of cases, with a subset showing upregulation. Peritumoral mucosa displayed similar dysregulation. Distinct stage-associated patterns emerged: peritumoral miR-144 was significantly reduced in advanced versus early disease (p = 0.013), whereas tumor miR-145 was significantly lower in advanced tumors (p = 0.004). No stage-related differences were detected for tumor miR-144 or peritumoral miR-145. miR-144 and miR-145 expression correlated moderately in both compartments (ρ = 0.40 tumor; ρ = 0.37 peritumor). ROC analysis revealed modest discriminatory potential (AUC 0.62-0.64). CONCLUSIONS:miR-144 and miR-145 exhibit distinct, stage-dependent dysregulation in laryngeal carcinoma. Tumor miR-145 and peritumoral miR-144 alterations support a dynamic model of field cancerization, suggesting potential biomarker roles in disease progression and risk assessment.

Background This study evaluates the feasibility, functional outcomes, and survival of surgical laryngeal preservation in advanced T3/T4 head and neck disease, based on the principle that an intact cricoarytenoid joint (CAJ) can provide sufficient functional reserve to compensate for resections involving other key contributors to swallowing. Methods Monocentric, observational study (STROBE compliant). 162 consecutive patients with advanced (T3/T4) laryngeal, hypopharyngeal, oropharyngeal, and tongue carcinomas treated surgically. Definitive surgery with either laryngectomy or laryngeal preservation (stage-matched subgroups), stratified by CAJ involvement and surgical approach (transoral vs. open). Results Of 162 patients, 95 (58%) underwent laryngectomy; 90% had CAJ invasion. Among 76 without CAJ involvement, 67 (88%) were suitable for preservation. Functional outcomes: 95.6% decannulated, 3% PEG, 4.4% tracheostomy dependence. Recurrence-free survival did not differ (85.1% preservation vs. 78.9% laryngectomy; log-rank p = 0.56). Overall survival tended lower in laryngectomy (57.9% vs. 79.1%; p = 0.16), explained by non–cancer mortality. Flap reconstruction was required in 43.4% of open non-laryngeal preservation cases, mostly T4 (p < 0.001). Open surgery showed inferior overall survival compared with transoral (70.0% vs. 92.6%; p = 0.038). Conclusion Functional upper airway preservation is feasible in most advanced head and neck cancers when CAJ is not engaged. An intact CAJ provides sufficient functional reserve to compensate for resections involving other key contributors to swallowing, enabling excellent oncologic outcomes with generally favorable functional recovery. Open preservation surgery carries greater morbidity and higher non–cancer-related mortality.

BACKGROUND AND OBJECTIVES:Laryngeal cancer is a common head and neck tumor burden, with no significant improvements in long term patient survival. Despite the progress of molecular genetics and oncology strategies, there is still a lack of biomarker use in routine clinical practice for early laryngeal cancer screening or diagnosis. miRNAs are explored as promising molecules, that could serve as liquid biopsy. Our goal is to explore the screening potential of miR-31-3p and miR-196a-5p in early- and advanced-stage laryngeal HPV-negative plasma samples. METHODS:In this study, 50 plasma samples obtained from early and advanced HPV-negative laryngeal cancer patients were included. The expression levels of mir-31-3p and miR-196a-5p were analyzed via TaqMan RT-qPCR. SPSS v27.0 was used for statistical analysis. RESULTS:For the first time, miR-31-3p and miR-196a-5p were analyzed in plasma samples from early HPV-negative primary LSCC patients. Both circulating miRNAs showed significantly elevated expression levels in early and advanced laryngeal cancer samples. miR-31-3p was significantly associated with T stages (p < 0.001) and N stages (p = 0.009). The ROC analysis revealed that miR-31-3p could significantly discriminate early-stage from advanced-stage LSCC with an AUC of 0.850 (95% CI: 0.743-0.956, p < 0.001) at an RQ cutoff of 2.03, achieving a sensitivity of 95.5% and a specificity of 64%. Nevertheless, miR-196a-5p was found to be significantly overexpressed in early-stage LSCC, which could contribute to the development of its screening potential. For the first time, both miRNAs revealed a significant positive correlation, which indicates that miR-31-3p and miR-196a-5p could coregulate cancerogenesis. CONCLUSIONS:In conclusion, the data revealed that miR-31-3p has greater potential as an LSCC screening marker in comparison to miR-196a-5p. Still, miR-196a-5p also showed promising results in early-stage laryngeal cancer monitoring. The utilization of circulating miR-31-3p or miR-196a-5p analysis could enable liquid biopsy approaches, with results potentially informing treatment monitoring strategies, personalized oncological protocols, and early diagnosis. These advancements could ultimately benefit patient outcomes by improving laryngeal organ preservation and survival rates.

Background and Clinical Significance: Petrous bone cholesteatoma is a rare and complex condition that poses significant challenges in terms of its diagnosis and treatment. This benign yet locally aggressive lesion can cause extensive destruction of the surrounding structures, potentially leading to serious complications. Case Presentation: We present a case of extensive petrous bone cholesteatoma involving nearly the entire skull base. High-resolution CT and MRI were used to assess the extent of the lesion and its relationship with critical neurovascular structures. The cholesteatoma extended from the petrous apex to the clivus, involving the internal auditory canal and Meckel’s cave, encasing the internal carotid artery, and compressing the brainstem. The surgical strategy included combined endoscopic transsphenoidal and transclival techniques with a retrolabyrinthine approach. The endoscopic component provided access to the anterior and central skull base regions, whereas the retrolabyrinthine approach allowed us to gain access to the posterior petrous area. Careful dissection was performed to separate the cholesteatoma from the internal carotid artery and the brainstem. Neuromonitoring was performed throughout the procedure to ensure cranial nerve integrity. This combined approach enabled gross total resection, and postoperative imaging confirmed successful tumor removal. The patient’s recovery was uneventful, and no new neurological deficits were observed. Conclusions: The successful management of this complex case demonstrates the efficacy and safety of combining endoscopic surgical approaches for extensive skull base cholesteatomas. This multi-corridor approach allows for maximal tumor resection while also minimizing the risks to critical neurovascular structures.

Introduction Nonmelanoma skin cancer is becoming more common and tend to increase worldwide, along with excessive exposure of the scalp and face to solar radiation and increasing life expectancy. In most patients, local surgical treatment is predominant. However, some patients can be diagnosed with cutaneous squamous cell carcinoma (SCC) with an increased risk of developing regional lymph node metastases. The parotid and upper cervical nodes are the most common sites for the development of metastases.

Theoretical basis: Patients presenting for microlaryngeal surgery may have a variety of comorbidities contributing to their voice symptoms and affecting anesthetic management. Results: Many patients presenting for laryngeal surgery have a long history of heavy smoking and drinking. Many patients who present for laryngeal surgery are elderly and have cardiovascular disease. The rate of difficult endotracheal intubation may reach almost 16% among patients presenting for ear, nose, or throat cancer surgery, which is on average six times higher than among the general surgical patient population. Loss of the airway on induction, requiring emergent cricothyrotomy or tracheostomy, can be sudden, especially in patients with critical airway obstruction. Prospective trials identify the incidence of dental trauma after suspension laryngoscopy at 0% to 6.5%, depending on the operator’s experience, methodology of the study, dental injury criteria, preexisting dentition status of the patient, and suspension technique used. Minor surgical complications, such as sore throat, mucosal injury (e.g., cuts, edema, hematoma), and cranial nerve dysfunction (e.g., lingual, glossopharyngeal, hypoglossal), are most commonly observed. The risk of postoperative airway compromise is significantly greater among the patients who underwent diagnostic laryngoscopy than those in the general surgical population. Conclusion: Patients presenting for microlaryngeal surgery may have a variety of intraoperative and postoperative complications.

INTRODUCTION Recently, miRNAs have become popular molecules used as non-invasive biomarkers in cancer diseases. AIM The aim of the study was to explore the expression of four miRNAs isoforms: miR-31-3p, miR-196a-5p, miR-210-3p and miR-424-5p in plasma and tissue samples from patients with advanced laryngeal squamous cell carcinoma (LSCC) and healthy controls. MATERIALS AND METHODS Fresh-frozen tumour and normal laryngeal tissue as well as plasma samples were obtained from 22 patients diagnosed with advanced LSCC. The control group included plasma samples from 21 cancer-free volunteers. Total RNA (including miRNAs) extraction, reverse transcription and real time qPCR were the laboratory techniques used in the study. The obtained results were analyzed using SPSS software v. 23. RESULTS We found that miR-31-3p, miR-196a-5p, and miR-210-3p levels were significantly elevated in laryngeal tumour tissue, but only the levels of miR-31-3p and miR-196a-5p were significantly upregulated in the plasma LSCC target group. Positive correlation was obtained for miR-31-3p (rs=0.443, p=0.039) and miR-196a-5p (rs=0.548; p=0.008) between plasma and adjacent tumour tissue LSCC samples. ROC analyses were used to evaluate the discriminative power of both miRNAs alone and in combination. The combination of miR-31-3p and miR-196a-5p showed best results with AUC=0.978 (95% CI: 0.945-1.000, p.

Introduction: Patients presenting for microlaryngeal surgery frequently have a difficult airway. The chosen approach to this airway depends on the pathology and the patient’s symptoms. The Aim of the study is to determine the safest anesthesiological approach to difficult airway during microlaryngeal surgery. Materials and Methods: A prospective cohort study including 200 patients undergoing microlaryngeal surgery in the Department of Otorhinolaryngology at the University Hospital “Queen Giovanna” - ISUL, Sofia, in the period 2014-2019; Medical University-Sofia. Preoperative examination of the larynx is performed in all patients by Storz 8402 ZX fiber optic laryngoscope with video capability. Results and discussion: In 76% of the patients the tumor mass causing obstruction is localized in the area of the larynx, and in 24% of them the tumor mass is localized in the area of the hypopharynx. In 20% of the patients with 3rd degree of laryngeal obstruction an awake tracheostomy is chosen as a primary approach because of impossible intubation. The same approach is chosen in all of the patients presenting with respiratory failure at rest. In 25% of the patients with tumor mass causing hypopharyngeal obstruction an awake tracheostomy is chosen as a primary approach because of impossible intubation. Conclusion The decision to proceed with an awake or asleep approach to an anticipated difficult airway depends on the degree of laryngeal or hypopharyngeal obstruction and the experience of the anesthesiologist.

The process of neoangiogenesis is one of the classic hallmarks of a cancer. Its intricate mechanisms have long been one of the major domains in cancer research and a hope for a therapeutic breakthrough. Last decade a new subgroup of non-coding RNA molecules was reported called microRNAs. Literally hundreds of new molecules in this class are being uncovered as pivotal regulators in virtually all intracellular processes. The aim of this study is to classify and review those microRNA molecules that have a role in the processes of tumor angiogenesis and map their places in the regulatory framework of the classical proangiogenic genes and their canonical cascades.

Purpose Laryngeal cancer is one of most common and aggressive head and neck cancers with poor prognosis and great necessity for improvement of treatment modalities. MicroRNAs (miRs) are among the most investigated molecules recently due to their potential as diagnostic and prognostic biomarkers in cancer. The purpose of our study was to explore the association of certain clinicopathological features with the expression levels of some known cancer associated non-coding (nc) RNAs: miR-21 and miR-31 in both of their isoforms, miR-145-5p, miR-55-5p, miR-196a-5p, miR-210-3p, miR-221-3p, miR-222-3p, miR-424-5p, lncRNA MALAT1 and lncRNA HOTAIR. Methods Expression levels of the chosen markers were investigated in laryngeal squamous cell carcinoma (LSCC) and normal samples in 82 Bulgarian patients via RT-qPCR, and the results were analyzed with SPSS v23.0 statistical software. Results All of the explored ncRNAs were significantly deregulated in LSCC samples, suggesting their involvement in laryngeal carcinogenesis. New significant association were found between the expression levels of miR-21-5p, miR-222-3p, HOTAIR and family history. Moreover, miR-424-5p showed potential as marker for subglottic LSCC location, and passenger miR-31-3p was significantly upregulated in well and moderately differentiated LSCC. Conclusion Our results enrich the knowledge about ncRNA involvement in LSCC tumorigenesis. Further studies are needed to evaluate the clinical utility of the differently expressed ncRNAs as potential diagnostic and prognostic biomarkers in LSCC.

During the last decade, next generation sequencing (NGS) became the major tool for detection of somatic mutations in cancer, but data about mutations in advanced laryngeal squamous carcinomas is still scarce. The aim of this study is to analyze the mutation profile of key oncogenes and tumour suppressor genes in advanced HPV-negative laryngeal squamous cell carcinoma. A total of 57 Bulgarian LSCC patients were included. DNA was isolated from fresh-frozen tissues. Targeted NGS was performed using TruSeq Amplicon Panel on Illumina platform, and data was analysed with VarSeq Software. Results revealed altogether 92 known pathogenic and likely pathogenic variants in 27 tumour-associated genes. Thirteen new variants were predicted to be pathogenic with four or more prediction programs. The most frequently mutated gene was TP53, with mutations in 84.2%, followed by MET in 19.3%, CDKN2A in 15.8%, PIK3CA in 14% and FBXW7 in 8.8% patients. Interestingly in eight of the supraglottic LSCC patients we found two TP53 mutations and in one subglottic LSCC patient - three TP53 mutations. For the first time the mutational spectrum of three LSCC sub-locations was analyzed and the supraglottis LSCC showed more mutated genes (n=20) compared to glottis (n=10) and subglottis (n=12) tumours. In 9% of the samples we found combined high-risk TP53 and RAS mutations, previously associated with poor overall survival and drug resistance. The analysis revealed that NOTCH1 mutations are not common for LSCC in comparison to other HNC loci. In addition, we found three common polymorphisms in TP53 (p.Pro72Arg), KDR (p.Gln472His) and KIT (p.Met541Leu) genes, strongly associated with angiogenesis, poor prognosis and metastasis and drug sensitivity in cancer diseases. In conclusion, NGS targeted sequencing enables discovery of new mutations in key genes relevant to LSCC, some of which might be useful in selection or development of more precise LSCC treatment approaches in the future.

The aim of this study is to evaluate which dysregulated angiomiRs compose the specific proangiogenic microRNA signature of advanced laryngeal cancer and review the literature. Thirty-six samples from twelve patients with advanced laryngeal carcinoma were collected. Total RNA was extracted and microRNA global profiling was performed using Agilent Technologies Microarray Kit. Fifty-nine microRNAs were found to have significantly different expression levels. Eleven microRNAs from the whole group were sorted as regulators of tumor angiogenesis (angiomiRs): seven were up-regulated-miR-1246, miR-181b 5p, miR-18a 5p, miR-21 3p, miR-210 3p, miR-503 5p, miR-93 5p and four were down-regulated-miR148a 5p, miR-145 5p, miR-204 5p, miR-125b 5p. For none of those microRNAs we found heterogeneity in tumor tissue. We are the first to report the specific proangiogenic microRNA signature in advanced laryngeal carcinoma and we confirm and amplify findings from previous studies that expand our perception of a specific "molecular state" of angiogenesis that is distinctive only for laryngeal cancer.

Theoretical basis: Microlaryngeal surgery can be conducted in an awake patient, frequently under conscious sedation, or with the patient anesthetized. The ventilation options under general anesthesia consist of “tube” (i.e., endotracheal intubation) and “tubeless” techniques, with the latter represented by the techniques of Spontaneous ventilation, Apneic intermittent ventilation (AIV), and Jet Ventilation (JV). Results: The use of a small (5.0-mm ID) MLT tube with positive-pressure ventilation remains the standard for airway management in most nonlaser microlaryngeal surgery, and it is associated with minimal or no intraoperative complications. Spontaneous ventilation is rarely used in adult microlaryngeal surgery, but it is commonly employed in the pediatric patient population. AIV remains a relatively popular technique for microlaryngeal surgical procedures of short duration in some surgical centers. Superimposed High-Frequency Jet Ventilation (SHFJV), which combines highfrequency and low-frequency ventilation modes, has been used effectively in surgical treatment of high-grade laryngeal and tracheal stenosis. Conclusion: General anesthesia for microlaryngeal surgery represents a unique example of close cooperation between the surgeon and the anesthesiologist.

Introduction: Successful anesthetic management of microlaryngeal cases requires a high degree of cooperation with the surgeon, a reciprocal understanding of the potential problems, and adequate preparation on both sides to meet the anticipated challenges that may arise. The Aim of the study is to determine the hemodynamic complications during microlaryngeal surgery. Materials and Methods: A 5-year prospective cohort study of 200 patients who underwent microlaryngeal surgery in the Department of ENT Surgery; University Hospital “Queen Giovanna”- ISUL; Medical University-Sofia. All patients were monitored and recorded for: Systolic blood pressure (SBP), Diastolic blood pressure (DBP); heart rate (HR); continuous electrocardiography (ECG). The above parameters were recorded and analyzed at predetermined time intervals: 5-th minute before intubation, every 5 minutes after intubation and 5-th minute after extubation. Results and discussion: Mean systolic blood pressure of the patients during the operation is 147.33 mmHg, mean diastolic blood pressure is 93.5 mmHg and mean pulse rate is 57.64 beats per minute. 49% of the patients have arterial hypertension I grade during the operation, 28% of them are with isolated arterial hypertension and 23% are with normal blood pressure. 40% of the patients had pulse rate between 45-60 beats per minute during putting on the tube of Kleinsasser, 29% of them had pulse rate>60 beats per minute during putting on the tube of Kleinsasser and 31% had pulse rate<45 beats per minute during putting on the tube of Kleinsasser. Conclusion: Microlaryngeal surgery is specific kind of surgery which is characterized by hypertensive hemodynamic. There is a risk of severe bradycardia after putting on the tube of Kleinsasser which can cause hemodynamic instability and even cardiac arrest if not corrected immediately.

Primary laryngectomy with postoperative radiotherapy is still the golden standard in treating laryngopharyngeal malignancies in advanced stage. Despite the promising results in some trials, recent studies show inferior long term results of larynx preservation protocols in this subgroup of patients. In the light of this debate, the aim of this study is to present the oncological outcomes of primary laryngectomy in patients with T4a and T4b laryngopharyngeal cancer.