Publications by authors named "Piero Nicolai"

254 Publications

Gene Expression Profiling of Olfactory Neuroblastoma Helps Identify Prognostic Pathways and Define Potentially Therapeutic Targets.

Cancers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, ASST Spedali Civili of Brescia, University of Brescia, 25123 Brescia, Italy.

Olfactory neuroblastoma (ONB) is a rare sinonasal neoplasm with a peculiar behavior, for which limited prognostic factors are available. Herein, we investigate the transcriptional pathways altered in ONB and correlate them with pathological features and clinical outcomes. We analyze 32 ONB patients treated with curative intent at two independent institutions from 2001 to 2019 for whom there is available pathologic and clinical data. We perform gene expression profiling on primary ONB samples and carry out functional enrichment analysis to investigate the key pathways associated with disease-free survival (DFS). The median age is 53.5 years; all patients undergo surgery and a pure endoscopic approach is adopted in the majority of cases (81.2%). Most patients have advanced disease (stages III-IV, 81.2%) and 84.4% undergo adjuvant (chemo)radiotherapy. The median follow-up is 35 months; 11 (26.8%) patients relapse. Clinical characteristics (gender, stage and Hyams' grade) are not associated with the outcomes. In contrast, TGF-beta binding, EMT, IFN-alpha response, angiogenesis, IL2-STAT5 and IL6-JAK-STAT3 signaling pathways are enriched in patients experiencing recurrence, and significantly associated with shorter DFS. Clustering of transcriptional profiles according to pathological features indicates two distinct molecular groups, defined by either cytokeratin-positive or -negative immunostaining. Definition of the characterizing ONB transcriptomic pathways may pave the way towards tailored treatment approaches.
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http://dx.doi.org/10.3390/cancers13112527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196700PMC
May 2021

When is a multidisciplinary surgical approach required in sinonasal tumours with cranial involvement?

Acta Otorhinolaryngol Ital 2021 Apr;41(Suppl. 1):S3-S17

Section of Otorhinolaryngology, Head and Neck Surgery, University of Padua, "Azienda Ospedaliera di Padova", Padua, Italy.

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http://dx.doi.org/10.14639/0392-100X-suppl.1-41-2021-01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172110PMC
April 2021

Endoscopic Subtemporal Epidural Key-Hole Approach: Quantitative Anatomic Analysis of Three Surgical Corridors.

World Neurosurg 2021 May 24. Epub 2021 May 24.

Unit of Neurosurgery, Department of Medical and Surgical Specialties, Radiologic Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: The endoscope-assisted subtemporal key-hole epidural approach (ESKEA) has been recently described. The aim of this study was to measure working volumes and exposure of key areas of the middle cranial fossa provided by this approach.

Methods: Four fresh frozen cadaver heads were dissected to analyze 3 modular corridors (1A, 1B, and 2) harvested through ESKEA. A step-by-step dissection was performed, and key anatomic landmarks were recorded. A GTxEyesII-ApproachViewer was used to quantify the working volume and exposure of 4 different regions (sphenoorbital, parasellar, superior petrous apex, and squamopetrous). For each corridor, 3 incremental degrees of temporal dural retraction (5, 10, and 15 mm) were tested.

Results: The working volume of all corridors progressively increased with degree of retraction: Corridors 1A, 1B, and 2 showed a gain in working volume of 21%, 27%, and 19% from 5 mm to 10 mm retraction, respectively, and a gain of 40%, 45%, and 44% from 5 mm to 15 mm retraction, respectively. The sphenoorbital area was exposed (27%-45%) through corridor 1A, and exposure significantly increased with the degree of retraction. Corridor 1B provided optimal exposure of parasellar areas (86%-100%) and superior petrous apex (70%-87%) regardless of the degree of retraction. The squamopetrous area was satisfactorily addressed through corridor 2 (88%) only with the highest degree of retraction.

Conclusions: ESKEA can be conceived as a modular approach: the 3 surgical corridors have specific working volumes, which are clearly influenced by the degree of temporal lobe retraction, and provide exposure of different middle cranial fossa areas.
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http://dx.doi.org/10.1016/j.wneu.2021.05.055DOI Listing
May 2021

The risk of recurrence in surgically treated head and neck squamous cell carcinomas: a conditional probability approach.

Acta Oncol 2021 May 20:1-6. Epub 2021 May 20.

Department of Medical Surgical and Health Sciences, Section of Otolaryngology, University of Trieste, Trieste, Italy.

Background: Over 50% of patients with head-and-neck squamous cell carcinoma (HNSCC) experience locoregional recurrence, which is associated with poor outcome. In the course of follow-up for patients surviving primary surgery for HNSCC, one might ask: What is the probability of recurrence in one year considering that the cancer has not yet recurred to date?

Materials And Methods: To answer this question, 979 patients surgically treated for HNSCC (i.e. cancer of the oral cavity, oropharynx, hypopharynx or larynx) between March 2004 and June 2018 were enrolled in a multicenter retrospective cohort study, followed up for death and recurrence over a 5 year period. The conditional probability of recurrence in 12 months - i.e. the probability of recurrence in the next 12 months given that, to date, the patient has not recurred - was derived from the cumulative incidence function (Aalen-Johansen method).

Results: Overall, the probability of recurrence was the highest during the first (17.3%) and the second years (9.6%) after surgery, declining thereafter to less than 5.0% a year thereafter. The probability of recurrence was significantly higher for stage III-IV HNSCCs than for stage I-II HNSCCs in the first year after surgery (20.4% versus 10.0%;  < 0.01), but not thereafter. This difference was most pronounced for oral cavity cancers. No significant differences were observed across different tumor sites.

Conclusion: This dynamic evaluation of recurrence risk in patients surgically treated for HNSCC provides helpful and clinically meaningful information, which can be useful to patients in planning their future life, and to clinicians in tailoring post-treatment surveillance according to a more personalized risk stratification.
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http://dx.doi.org/10.1080/0284186X.2021.1925343DOI Listing
May 2021

Step-by-Step Cadaver Dissection and Surgical Technique for Compartmental Tongue and Floor of Mouth Resection.

Front Oncol 2021 23;11:613945. Epub 2021 Apr 23.

Department of Otorhinolaryngology - Head and Neck Surgery, "San Maurizio" Hospital, Bolzano, Italy.

Background: The aim of oral cancer surgery is tumor removal within clear margins of healthy tissue: the latter definition in the literature, however, may vary between 1 and 2 cm, and should be intended in the three dimensions, which further complicates its precise measurement. Moreover, the biological behavior of tongue and floor of mouth cancer can be unpredictable and often eludes the previously mentioned safe surgical margins concept due to the complexity of tongue anatomy, the intricated arrangements of its intrinsic and extrinsic muscle fibers, and the presence of rich neurovascular and lymphatic networks within it. These structures may act as specific pathways of loco-regional tumor spread, allowing the neoplasm to escape beyond its visible macroscopic boundaries. Based on this concept, in the past two decades, compartmental surgery (CS) for treatment of oral tongue and floor of mouth cancer was proposed as an alternative to more traditional transoral resections.

Methods: The authors performed three anatomical dissections on fresh-frozen cadaver heads that were injected with red and blue-stained silicon. All procedures were documented by photographs taken with a professional reflex digital camera.

Results: One of these step-by-step cadaver dissections is herein reported, detailing the pivotal points of CS with the aim to share this procedure at benefit of the youngest surgeons.

Conclusions: We herein present the CS step-by-step technique to highlight its potential in improving loco-regional control by checking all possible routes of tumor spread. Correct identification of the anatomical space between tumor and nodes (T-N tract), spatial relationships of extrinsic tongue muscles, as well as neurovascular bundles of the floor of mouth, are depicted to improve knowledge of this complex anatomical area.
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http://dx.doi.org/10.3389/fonc.2021.613945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104033PMC
April 2021

Endoscopic-assisted multi-portal compartmental resection of the masticatory space in oral cancer: Anatomical study and preliminary clinical experience.

Oral Oncol 2021 Jun 4;117:105269. Epub 2021 Apr 4.

Unit of Otorhinolaryngology, "San Maurizio" Hospital of Bolzano, Bolzano, Italy.

Objectives: To present an anatomical cadaver dissection study and our preliminary surgical experience with endoscopic-assisted multi-portal compartmental resection of the masticatory space (MS) in locally advanced oral squamous cell carcinoma (OSCC) of the retromolar area.

Materials And Methods: Two fresh-frozen cadaver heads were dissected in the Laboratory of Anatomy to define the surgical steps of an endoscopic-assisted multi-portal compartmental approach to the MS. After this preclinical anatomical study, patients affected by locally advanced OSCC originating from the retromolar area with extension to the MS were prospectively enrolled and operated at two Italian referral centers for head and neck cancer between October 2019 and May 2020.

Results: Surgical technique of endoscopic-assisted multi-portal compartmental resection of the MS was preclinically defined step by step in 3 phases: transnasal, transoral/trancervical, and multi-portal. Compartmental resection of the MS was successfully completed in all specimens (4 MSs dissected). The surgical technique was subsequently applied in 3 patients affected by primary OSCC of the retromolar area, providing satisfactory results in terms of negative resection margins and local control.

Conclusions: Multi-portal compartmental resection of the MS combining the transnasal and transoral/transcervical corridors is technically feasible. Such an approach to the MS in locally advanced OSCC provides different angles of incidence to the target and full control of tumor margins.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105269DOI Listing
June 2021

Tumor-associated neutrophils (TANs) in human carcinoma-draining lymph nodes: a novel TAN compartment.

Clin Transl Immunology 2021 16;10(2):e1252. Epub 2021 Feb 16.

Section of Pathology Department of Molecular and Translational Medicine University of Brescia Brescia Italy.

Objectives: The role of tumor-associated neutrophils (TANs) in the nodal spread of cancer cells remains unexplored. The present study evaluates the occurrence and clinical significance of human nodal TANs.

Methods: The relevance, derivation, phenotype and interactions of nodal TANs were explored a large immunohistochemical analysis of carcinoma-draining lymph nodes, and their clinical significance was evaluated on a retrospective cohort of oral squamous cell carcinomas (OSCC). The tumor-promoting function of nodal TAN was probed in the OSCC TCGA dataset combining TAN and epithelial-to-mesenchymal transition (EMT) signatures.

Results: The pan-carcinoma screening identified a consistent infiltration (59%) of CD66b  TANs in tumor-draining lymph nodes (TDLNs). Microscopic findings, including the occurrence of intra-lymphatic conjugates of TANs and cancer cells, indicate that TANs migrate through lymphatic vessels. experiments revealed that OSCC cell lines sustain neutrophil viability and activation via release of GM-CSF. Moreover, by retrospective analysis, a high CD66b TAN density in M-TDLNs of OSCC ( = 182 patients) predicted a worse prognosis. The analysis of the OSCC-TCGA dataset unveiled that the expression of a set of neutrophil-specific genes in the primary tumor (PT) is highly associated with an EMT signature, which predicts nodal spread. Accordingly, in the PT of OSCC cases, CD66bTANs co-localised with PDPNS100A9 EMT-switched tumor cells in areas of lymphangiogenesis. The pro-EMT signature is lacking in peripheral blood neutrophils from OSCC patients, suggesting tissue skewing of TANs.

Conclusion: Our findings are consistent with a novel pro-tumoral TAN compartment that may promote nodal spread EMT, through the lymphatics.
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http://dx.doi.org/10.1002/cti2.1252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886597PMC
February 2021

Predictive nomograms for oral tongue squamous cell carcinoma applying the American Joint Committee on Cancer/Union Internationale Contre le Cancer 8th edition staging system.

Head Neck 2021 Apr 2;43(4):1043-1055. Epub 2021 Feb 2.

Department of Head and Neck Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Kochi, India.

Background: Nomograms applying the 8th edition of the TNM staging system aimed at predicting overall (OS), disease-specific (DSS), locoregional recurrence-free (LRRFS) and distant recurrence-free survivals (DRFS) for oral tongue squamous cell carcinoma (OTSCC) are still lacking.

Methods: A training cohort of 438 patients with OTSCC was retrospectively enrolled from a single institution. An external validation set of 287 patients was retrieved from two independent institutions.

Results: Internal validation of the multivariable models for OS, DSS, DRFS and LRRFS showed a good calibration and discrimination results with optimism-corrected c-indices of 0.74, 0.75, 0.77 and 0.70, respectively. The external validation confirmed the good performance of OS, DSS and DRFS models (c-index 0.73 and 0.77, and 0.73, respectively) and a fair performance of the LRRFS model (c-index 0.58).

Conclusions: The nomograms herein presented can be implemented as useful tools for prediction of OS, DSS, DRFS and LRRFS in OTSCC.
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http://dx.doi.org/10.1002/hed.26554DOI Listing
April 2021

Sinonasal cancer encroaching the orbit: Ablation or preservation?

Oral Oncol 2021 03 28;114:105185. Epub 2021 Jan 28.

Section of Otorhinolaryngology - Head and Neck Surgery, Department of Neurosciences, University of Padua - "Azienda Ospedaliera di Padova", Padua, Italy.

Background: Encroachment on the orbital cavity represents a challenge in the management of sinonasal cancer. Criteria guiding orbital preservation lack univocal consensus. Stage of orbital involvement is best assessed through magnetic resonance imaging (MRI).

Methods: Patients affected by orbit-encroaching sinonasal cancer with available preoperative MRI, receiving surgery-based treatment at the University of Brescia between May 2005 and October 2018 were included. All cases were reviewed by expert radiologists and pathologists. Diagnostic performance of MRI was calculated using pathological information as reference. Survival analysis was performed.

Results: The study included 123 patients. The orbit was abutted in 53 (43.1%) patients, whereas orbital invasion reached the periorbit in 18 (14.6%), extraconal fat and/or medial lacrimal sac in 29 (23.6%), extrinsic ocular muscles in 7 (5.7%), intraconal compartment in 4 (3.3%), and orbital apex in 12 (9.8%). Seventy-six (61.8%) patients received orbit-sparing surgery, 47 (38.2%) underwent orbital ablation (OA). Accuracy of MRI in detecting involvement by cancer was ≥80.0% for the orbital wall, extraconal fat, and muscles, and <80.0% for the periorbit and intraconal compartment. Previous surgery, neoadjuvant chemotherapy, and perineural invasion decreased MRI accuracy. Age, histology, tumor grade, pT category, N status, perineural invasion, orbital invasion stage, and need for OA were found to affect prognosis. Five-year orbital dysfunction-free survival was 92.8%.

Conclusion: Conservative management of sinonasal cancers encroaching the orbit is feasible. MRI is essential to preoperatively stage orbital invasion, yet with some limitation. Given the dismal prognosis despite aggressive surgery, neoadjuvant non-surgical therapies should be considered in patients requiring OA.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105185DOI Listing
March 2021

Advanced lung cancer inflammation index and its prognostic value in HPV-negative head and neck squamous cell carcinoma: a multicentre study.

Support Care Cancer 2021 Jan 29. Epub 2021 Jan 29.

Department of Neurosciences, Section of Otolaryngology, University of Padova, Treviso, Italy.

Purpose: The aim of this study is to evaluate the prognostic value of pre-treatment advanced lung cancer inflammation index (ALI) in patients with HPV-negative HNSCC undergoing up-front surgical treatment.

Methods: The present multi-centre, retrospective study was performed in a consecutive cohort of patients who underwent upfront surgery with or without adjuvant (chemo)-radiotherapy for head and neck squamous cell carcinoma (HNSCC). Patients were stratified by ALI, and survival outcomes were compared between groups. In addition, the prognostic value of ALI was compared with two other indices, the prognostic nutritional index (PNI) and systemic inflammatory index (SIM).

Results: Two hundred twenty-three patients met the inclusion criteria (151 male and 72 female). Overall and progression-free survival were significantly predicted by ALI < 20.4 (HR 3.23, CI 1.51-6.90 for PFS and HR 3.41, CI 1.47-7.91 for OS). Similarly, PNI < 40.5 (HR = 2.43, 95% CI: 1.31-4.51 for PFS and HR = 2.40, 95% CI: 1.19-4.82 for OS) and SIM > 2.5 (HR = 2.51, 95% CI: 1.23-5.10 for PFS and HR = 2.60, 95% CI: 1.19-5.67 for OS) were found to be significant predictors. Among the three indices, ALI < 20.4 identified the patients with the worst 5-year outcomes. Moreover, patients with a combination of low PNI and low ALI resulted to be a better predictor of progression (HR = 5.26, 95% CI: 2.01-13.73) and death (HR = 5.68, 95% CI: 1.92-16.79) than low ALI and low PNI considered alone.

Conclusions: Our results support the use of pre-treatment ALI, an easily measurable inflammatory/nutritional index, in daily clinical practice to improve prognostic stratification in surgically treated HPV-negative HNSCC.
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http://dx.doi.org/10.1007/s00520-020-05979-9DOI Listing
January 2021

A new landmark for lingual artery identification during transoral surgery: Anatomic-radiologic study.

Head Neck 2021 May 25;43(5):1487-1498. Epub 2021 Jan 25.

Unit of Otorhinolaryngology - Head and Neck Surgery, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.

Background: A landmark for the identification of the lingual artery (LA) through a transoral perspective can provide surgeons with an easy method to prevent and manage intraoperative bleeding during transoral approach to the base of tongue (BOT).

Methods: Thirteen tongue and five head and neck specimens were dissected to identify and assess the reliability of the lingual point (LP) as a new landmark for the LA at BOT. The pathway of 42 LAs was radiologically evaluated; axial depth and vertical offset were measured for each LA.

Results: Dissection study: a description of LP is provided; the LA was easily identified in all specimens (36/36 sides) using LP as a landmark. Radiologic study: the mean depth of the LA was 4.2 mm, the mean vertical offset was 1.3 mm.

Conclusions: LP is a simple and reliable landmark for identification of the LA, potentially helping surgeons to prevent and manage intraoperative bleeding.
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http://dx.doi.org/10.1002/hed.26606DOI Listing
May 2021

Transorbital endoscopic approaches to the skull base: a systematic literature review and anatomical description.

Neurosurg Rev 2021 Jan 22. Epub 2021 Jan 22.

Section of Otorhinolaryngology - Head and Neck Surgery, Department of Neurosciences, University of Padua, Padua, Italy.

Transorbital endoscopic approaches are increasing in popularity as they provide corridors to reach various areas of the ventral skull base through the orbit. They can be used either alone or in combination with different approaches when dealing with the pathologies of the skull base. The objective of the current study is to evaluate the surgical anatomy of transorbital endoscopic approaches by cadaver dissections as well as providing objective clinical data on their actual employment and morbidity through a systematic review of the current literature. Four cadaveric specimens were dissected, and step-by-step dissection of each endoscopic transorbital approach was performed to identify the main anatomic landmarks and corridors. A systematic review with pooled analysis of the current literature from January 2000 to April 2020 was performed and the related studies were analyzed. Main anatomical landmarks are presented based on the anatomical study and systematic review of the literature. With emphasis on the specific transorbital approach used, indications, surgical technique, and complications are reviewed through the systematic review of 42 studies (19 in vivo and 23 anatomical dissections) including 193 patients. In conclusion, transorbital endoscopic approaches are promising and appear as feasible techniques for the surgical treatment of skull base lesions. Surgical anatomy of transorbital endoscopic approaches can be mastered through knowledge of a number of anatomical landmarks. Based on data available in the literature, transorbital endoscopic approaches represent an important complementary that should be included in the armamentarium of a skull base team.
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http://dx.doi.org/10.1007/s10143-020-01470-5DOI Listing
January 2021

Genome-wide study of salivary miRNAs identifies miR-423-5p as promising diagnostic and prognostic biomarker in oral squamous cell carcinoma.

Theranostics 2021 1;11(6):2987-2999. Epub 2021 Jan 1.

'Angelo Nocivelli' Institute of Molecular Medicine, University of Brescia and ASST Spedali Civili di Brescia, Brescia, Italy.

Survival rates of oral squamous cell carcinoma (OSCC) remained substantially unchanged over the last decades; thus, additional prognostic tools are strongly needed. Salivary miRNAs have emerged as excellent non-invasive cancer biomarker candidates, but their association with OSCC prognosis has not been investigated yet. In this study, we analyzed global salivary miRNA expression in OSCC patients and healthy controls, with the aim to define its diagnostic and prognostic potential. Saliva was collected from patients with newly diagnosed untreated primary OSCC and healthy controls. Global profiling of salivary miRNAs was carried out through a microarray approach, while signature validation was performed by quantitative real-time PCR (RT-qPCR). A stringent statistical approach for microarray and RT-qPCR data normalization was applied. The diagnostic performance of miRNAs and their correlation with OSCC prognosis were comprehensively analyzed. In total, 25 miRNAs emerged as differentially expressed between OSCC patients and healthy controls and, among them, seven were significantly associated with disease-free survival (DFS). miR-106b-5p, miR-423-5p and miR-193b-3p were expressed at high levels in saliva of OSCC patients and their combination displays the best diagnostic performance (ROC - AUC = 0.98). Moreover, high expression of miR-423-5p was an independent predictor of poor DFS, when included in multivariate survival analysis with the number of positive lymph nodes - the only significant clinical prognosticator. Finally, we observed a significant decrease in miR-423-5p expression in matched post-operative saliva samples, suggesting its potential cancer-specific origin. Salivary miRNAs identified in our cohort of patients show to be accurate in OSCC detection and to effectively stratify patients according to their likelihood of relapse. These results, if validated in an independent set of patients, could be particularly promising for screening/follow-up of high-risk populations and useful for preoperative prognostic assessment.
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http://dx.doi.org/10.7150/thno.45157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806472PMC
January 2021

[F]FDG PET/MRI versus contrast-enhanced MRI in detecting regional HNSCC metastases.

Ann Nucl Med 2021 Feb 17;35(2):260-269. Epub 2021 Jan 17.

Nuclear Medicine Unit, Department of Medicine DIMED, Padova University Hospital, Padua, Italy.

Objective: To compare the accuracy of contrast-enhanced MRI using established dimensional and morphological criteria versus integrated [F]FDG PET/MRI in identifying regional lymph node metastases in patients with newly diagnosed head and neck squamous cell carcinoma (HNSCC). For this purpose, we compare MRI and PET/MRI using the histopathological findings in dissected lymph nodes as the gold standard.

Methods: We retrospectively reviewed 26 patients with histologically proven HNSCC who underwent gadolinium-enhanced [F]FDG PET/MRI as part of their staging. All neck lymph nodes were classified on MRI using dimensional and/or morphological criteria. Then, they were jointly assessed by a nuclear medicine physician and a radiologist using integrated [F]PET/MR images. ROC curves were obtained to compare the techniques. Lymph node histopathology was considered as the reference standard.

Results: Out of 865 lymph nodes, 35 were malignant at histopathology (3 with micro-metastases). Sensitivity and specificity were 48.6% and 99.5% for MRI using dimensional criteria; 60.0% and 99.6% for MRI using morphological criteria; 60.0% and 99.4% for MRI using both; and 74.3% and 97.6% for PET using MR as anatomic localization. The area under the ROC curve was higher for PET and MRI localization (0.859) than for MRI using dimensional (0.740; p < 0.05), or morphological (0.798; p < 0.05), or both criteria (0.797; p < 0.05). PET/MR using a PET SUVmax cutoff of 5.7 combined with MRI using dimensional and/or morphological criteria reached high values for accuracy (98.2%), NPV (98.2%), and PPV (95.2%).

Conclusions: Compared with traditional contrast-enhanced MRI or PET alone, integrated PET/MRI could improve diagnostic accuracy in detecting metastatic lymph nodes in patients with HNSCC.
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http://dx.doi.org/10.1007/s12149-020-01565-5DOI Listing
February 2021

Management of anterior fossa cephaloceles.

J Neurosurg Sci 2021 Apr 15;65(2):140-150. Epub 2020 Dec 15.

Section of Otorhinolaryngology, Head and Neck Surgery, Department of Neurosciences, University of Padua, Padua, Italy.

Skull base cephaloceles (SBCs) are defined as herniation of intracranial content through the skull base and are classified based on composition, etiology, and topographic location. Anterior SBCs frequently protrude in the sinonasal cavity, and consequently are at potential risk of infection. Therefore, the current recommendation is to treat SBCs with the primary intent of preventing meningitis, and surgery represents the mainstay of treatment. Anterior SBCs may display a wide spectrum of severity and complexity, and in each case the risks and benefits of surgical approaches are to be carefully weighted based on thorough assessment of symptoms, age, general conditions, location and size of the lesion, as well as expertise of the surgeon. In the last 30 years, the evolution and diffusion of transnasal endoscopic surgery have substantially changed the surgical management of the majority of SBC. In the past, they were treated exclusively with open transcranial approaches that may be burdened by relevant morbidity and risk for severe complications. The transnasal endoscopic corridor now provides easy access to the lesion and different reconstructive strategies using endonasal pedicled flaps, without any external incision, cranioplasty or brain manipulation. However, there are still scenarios in which an exclusive transnasal endoscopic route is contraindicated. The aim of the present review was to provide an overview on the comprehensive management of anterior SBC, with a particular focus on lesions suitable for endoscopic surgery. Furthermore, special aspects of SBC management in children and adults will be highlighted.
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http://dx.doi.org/10.23736/S0390-5616.20.05099-7DOI Listing
April 2021

Differentiated Thyroid Cancer: The Role of ATA Nodal Risk Factors in N1b Patients.

Laryngoscope 2021 03 10;131(3):E1029-E1034. Epub 2020 Sep 10.

Unit of Otorhinolaryngology-Head and Neck Surgery, University of Brescia, Brescia, Italy.

Objectives/hypothesis: Nodal involvement is frequent in patients with differentiated thyroid cancers (DTCs), but its prognostic relevance is not univocal. Some characteristics of nodal metastases can increase the risk of recurrence. We attempted to quantify the impact on survival of nodal factors included in the American Thyroid Association (ATA) risk stratification system in N1b patients with DTC.

Study Design: Retrospective study.

Methods: A retrospective analysis of patients affected by DTC who underwent therapeutic lateral neck dissection (ND) was performed. The impact on the prognosis of the number of positive lymph nodes (LNs), dimension of nodal metastasis, and microscopic and macroscopic extranodal extension (miENE and maENE, respectively) was investigated.

Results: The study included 347 N1b patients who underwent 401 therapeutic lateral NDs. Mean number of positive LNs was nine, mean nodal ratio was 0.27, and mean diameter of metastasis was 15.5 mm. ENE was detected in 25.9% of patients (22.5% miENE and 3.5% maENE). In univariate analysis, the presence of maENE had an impact on disease specific survival (DSS) (P = .023); increasing number of positive LNs affected DSS and locoregional control (LRC) (P = .009 and =.006, respectively); increasing metastatic node dimension was a risk factors for overall survival, DSS, and metastases free survival (MFS) (P = .05, =.013 and =.016). In multivariate analysis, number of positive LNs and LN dimension were independent risk factors for LRC and MFS, respectively (HR 1.1, P = .028; HR 1.1, P = .026).

Conclusions: In our analysis on a cohort of N1b patients, the number of positive LNs and LN dimension were confirmed as independent risk factors for locoregional and distant recurrence, respectively.

Level Of Evidence: 4 Laryngoscope, 131:E1029-E1034, 2021.
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http://dx.doi.org/10.1002/lary.29057DOI Listing
March 2021

Early Postoperative Magnetic Resonance in the Diagnosis of Persistent Juvenile Angiofibroma.

Laryngoscope 2020 Nov 27. Epub 2020 Nov 27.

Section of Otorhinolaryngology-Head and Neck Surgery, Department of Neurosciences, University of Padua, Padua, Italy.

Objectives/hypothesis: Despite improvements in the treatment of juvenile angiofibroma (JA), the rate of persistence (pJA) is still not negligible. In the present study, we assessed the value of early postoperative magnetic resonance imaging (MRI) in depicting unintentional pJAs and designed a MRI-driven decisional flow-chart for pJA management and follow-up.

Study Design: Observational study.

Methods: Patients undergoing early postoperative MRI after endoscopic resection of JA in the Unit of Otorhinolaryngology - ASST Spedali Civili, University of Brescia from 2007 to 2017 were enrolled. MRI was defined as negative or positive based on defined radiological criteria. The diagnostic performance of MRI was evaluated.

Results: The analysis included 26 patients, with a mean age of 16.5 years (range, 11-25). Early MRI was negative for pJA in 21 (80.8%) patients and positive in five (19.2%). No patient with a negative finding was found positive at subsequent follow-up MRIs. The accuracy of a positive finding was confirmed by pathologic examination (three cases) or follow-up MRIs (two cases). The diagnostic performance of MRI was excellent with sensitivity and specificity of 100%. An MRI-driven flow-chart for pJA management and follow-up was designed.

Conclusions: Early postoperative MRI demonstrated a high diagnostic accuracy in the detection of unintentional pJA. Our MRI-driven strategy and decisional flow-chart could aid in the decision-making process in the management of pJA and definition of postoperative surveillance.

Level Of Evidence: 4 Laryngoscope, 2020.
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http://dx.doi.org/10.1002/lary.29293DOI Listing
November 2020

Temporal bone carcinoma: testing the prognostic value of a novel clinical and histological scoring system.

Eur Arch Otorhinolaryngol 2020 Nov 24. Epub 2020 Nov 24.

Department of Neuroscience DNS, Otolaryngology Section, Padova University, Via Giustiniani 2, 35128, Padova, Italy.

Purpose: Our group recently proposed the novel Padova prognostic scoring system for temporal bone carcinoma (TBSCC) that considers: the revised Pittsburgh staging system; radiological dura mater involvement; non-anterior spread (medial, inferior or posterior into the temporal bone and skull base) of T4 tumors; and histological grade. The aim of the present study was to validate this prognostic TBSCC scoring system in a case series selected from the literature.

Methods: A search was run to identify studies on TBSCC reporting the variables included in our score for each patient. Then our system was applied to the data extracted.

Results: Only two published investigations reported all the clinical and pathological data required for our scoring system. In one series from the Gruppo Otologico in Piacenza (Italy), a significantly higher recurrence rate (p = 0.008), shorter disease-free survival (DFS) (p = 0.001), higher disease-specific mortality (DSM) (p = 0.006), and shorter disease-specific survival (DSS) (p = 0.004) were associated with scores ≥ 5. Receiver operating curve (ROC) analysis showed an AUC of 0.804 for TBSCC recurrence, and 0.832 for DSM. In a series from Kyushu University Hospital (Japan), a significantly higher DSM (p = 0.018) and shorter DSS (p = 0.021) were associated with scores ≥ 5. ROC analysis showed an AUC of 0.812 for tumor relapse and 0.790 for DSM.

Conclusion: Our TBSCC Padova scoring system confirmed its validity when applied to the only two international TBSCC series providing the required data. These preliminary results need to be confirmed in a multi-center prospective setting.
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http://dx.doi.org/10.1007/s00405-020-06489-4DOI Listing
November 2020

Elective neck dissection in primary parotid carcinomas: A systematic review and meta-analysis.

J Oral Pathol Med 2021 Feb 26;50(2):136-144. Epub 2020 Dec 26.

Department of Otolaryngology-Head and Neck Surgery, Giovanni Borea Civil Hospital, Sanremo, Italy.

Background: To estimate the rate of occult cervical lymph node metastases in cN0 patients affected by primary parotid carcinomas and to scrutinize the evidence on the indication and extent of elective neck dissection in these neoplasms.

Methods: Medline, Embase, Web of Science, Cochrane Library and Scopus were searched until August 31, 2020, to identify studies reporting the use of elective neck dissection in the management of malignant parotid tumours. The PRISMA checklist was used. A single arm meta-analysis was then made to determine the pooled rate of occult lymph node metastases. Risk of bias of the included studies was assessed through the ROBINS-E tool.

Results: The initial search returned 20 541 articles, of which twelve met the inclusion criteria and were included in the meta-analysis. They comprised 1310 patients with parotid carcinoma, of whom 542 cN0 underwent elective neck dissection, which led to the diagnosis of lymph node metastasis (pN+/cN0) in 113 cases. Meta-analysis of the results of elective neck dissection showed an overall rate of occult metastases of 0.22 (99% CI: 0.14-0.30). Locally advanced or high-grade tumours were the commonest indications for elective neck dissection in the included studies. The most dissected lymph node levels were I-II-III, and level II was the commonest site of occult nodal metastases.

Conclusions: An occult metastasis rate of 0.22 (99% CI: 0.14-0.30) represents a not negligible percentage value, which should encourage further research to outline the most appropriate elective neck management in cN0 patients with parotid carcinomas.
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http://dx.doi.org/10.1111/jop.13137DOI Listing
February 2021

Prognostic impact of neutrophils-to-lymphocytes ratio (NLR), PD-L1 expression, and tumor immune microenvironment in laryngeal cancer.

Ann Diagn Pathol 2021 Feb 5;50:151657. Epub 2020 Nov 5.

Department of Neuroscience DNS, Otolaryngology Section, University of Padova, Padova, Italy. Electronic address:

Purpose: In laryngeal carcinoma (LSCC), tumor immune microenvironment is attracting increasing interest, given the recent progresses in immunotherapy. Immune cells migrate to tumors as a result of a tumor antigen-induced immune reaction and cancer cells recruit immune regulatory cells to induce an immunosuppressive network, resulting in the escape from host immunity. This interaction reflects both on tumor microenvironment and systemic inflammatory status. Blood neutrophil-to-lymphocyte ratio (NLR), reflecting a highly pro-inflammatory status, has been related to worse oncological survival outcomes. The aim of this study was to analyze in LSCC the relationship between circulating inflammatory cells (also in terms of NLR) and tumor immune microenvironment histopathological features (programmed cell death ligand 1 [PD-L1] expression, and tumor-infiltrating lymphocytes [TILs]), also investigating their clinical-pathological and prognostic significance.

Methods: Blood pre-operative NLR, and, at pathology, PD-L1 (in terms of combined positive score [CPS]) and TILs were assessed on 60 consecutive cases of LSCC.

Results: Blood NLR, neutrophils, and lymphocytes counts showed a significant value in predicting DFS and recurrence risk. Moreover, PD-L1 CPS ≥ 1 and TILs count rate ≥30% were associated with higher disease-free survival (DFS) and reduced recurrence risk. A logistic regression model found a significant positive association between increasing NLR values, and PD-L1 CPS < 1 and TILs count rate <30%.

Conclusions: Further studies are needed to better characterize the role of pre-operative blood NLR in association with PD-L1 expression and tumor immune microenvironment features as prognostic factors and markers of anti-tumor immune response in LSCCs, also with regard to the effectiveness of immunotherapeutic protocols.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151657DOI Listing
February 2021

The impact of nodal status in major salivary gland carcinoma: A multicenter experience and proposal of a novel N-classification.

Oral Oncol 2021 01 30;112:105076. Epub 2020 Oct 30.

Section of Otorhinolaryngology - Head and Neck Surgery, Department of Neurosciences, University of Padua, Padua, Italy.

Objectives: Despite differences in oncological behavior, the 8th edition of AJCC TNM staging currently proposes the same N-classification for major salivary glands (MSG) carcinoma and squamous cell carcinoma of the upper aerodigestive tract. The present study aims to investigate a more reliable definition of N-categories for MSG carcinoma.

Materials And Methods: A retrospective multicenter study was performed, including 307 patients treated for primary MSG carcinoma from 1995 to 2019. Outcome measures included overall survival (OS), disease specific survival, and local, regional, and distant recurrence. Survival analysis was performed using log-rank test and Cox proportional-hazards model. Overall number (ON) and largest diameter (LD) of nodal metastases, including intra-parotid metastases, were considered to develop three novel proposals of N-classification; their performance were compared with the current TNM staging using Akaike information criterion (AIC), Bayesian information criterion (BIC), and Nagelkerke pseudo-R.

Results: Intra-parotid nodes, ON and LD of nodal metastases emerged as major prognosticators for OS, while extra-nodal extension did not impact on any survival. The current N-classification did not show a satisfactory OS stratification. Three novel N-classifications were developed according to number of metastatic nodes (0 vs 1-3 vs ≥ 4) and/or their maximum diameter (<20 mm vs ≥ 20 mm). They all showed better accuracy in OS stratification, and achieved better AIC, BIC and Nagelkerke pseudo-R indices when compared to current N-classification.

Conclusion: All the proposed N-classifications improved OS stratification and could help in defining a specific N-classification for MSG carcinoma. Their validation and assessment in an external cohort is needed.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105076DOI Listing
January 2021

Health-Related Quality of Life in Patients With ANCA-Associated Vasculitis and Sinonasal Involvement: A Single-Center Cross-Sectional Study.

J Clin Rheumatol 2020 Oct 30. Epub 2020 Oct 30.

Rheumatology Unit, Department of Medicine DIMED, University of Padua, Padua, Italy.

Background/objective: The aim of this study was to assess the impact of sinonasal morbidity on quality of life (QoL) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV).

Methods: This cross-sectional case-control study enrolled 71 patients-44 AAV cases with (ear, nose, and throat [ENT]-AAV) or without ENT involvement (non-ENT-AAV) undergoing multidisciplinary evaluations and 27 chronic rhinosinusitis (CRS) cases. Three validated QoL questionnaires (Sino-Nasal Outcomes Test-22 [SNOT-22], Nasal Obstruction Symptom Evaluation [NOSE], and Short-Form 36) were administered, and the 3 groups were compared.

Results: The ENT-AAV patients were significantly younger (p = 0.01), with less antineutrophil cytoplasmic antibody positivity frequency (p = 0.035) and lower renal involvement (p = 0.003) than the non-ENT-AAV patients.The SNOT-22 questionnaire demonstrated significantly greater sinonasal morbidity in ENT-AAV patients compared with CRS patients (p < 0.001). The NOSE score of ENT-AAV patients was comparable to those of CRS patients, but higher than that of non-ENT-AAV patients (p < 0.001). The SNOT-22 and NOSE scores positively correlated with disease activity (p = 0.037; p = 0.004, respectively). Short-Form 36 domain-by-domain analysis revealed a significantly poorer QoL in ENT-AAV patients, especially with physical functioning being progressively impaired in CRS, non-ENT-AAV, and ENT-AAV patients (p < 0.001). No significant differences in QoL came to light when AAV patients were stratified according to current systemic o local treatments.

Conclusions: The QoL in AAV patients is significantly reduced, especially in the presence of ENT involvement. The AAV-related nasal morbidity is consistent and comparable to that reported by CRS patients. It significantly affects patients' QoL and in particular social functioning, leading to limitation in daily/work activities. Organ-focused questionnaires and multidisciplinary management are warranted to pursue a treat-to-target approach in these patients.
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http://dx.doi.org/10.1097/RHU.0000000000001630DOI Listing
October 2020

COVID-19 screening protocols for preoperative assessment of head and neck cancer patients candidate for elective surgery in the midst of the pandemic: A narrative review with comparison between two Italian institutions.

Oral Oncol 2021 01 14;112:105043. Epub 2020 Oct 14.

Section of Otorhinolaryngology-Head and Neck Surgery, Azienda Ospedaliera di Padova, University of Padua, Padua, Italy.

Background: Preoperative screening had a key role in planning elective surgical activity for head and neck cancer (HNC) during the COVID-19 pandemic.

Methods: All patients undergoing surgery for HNC at two Italian referral hospitals (University of Padua and National Cancer Institute [NCI]) during the peak of the COVID-19 epidemic in Italy were included. Accuracy of screening protocols was assessed.

Results: In the Padua protocol, 41 patients were screened by pharyngeal swab. The entire sample (100%) was admitted to surgery, diagnostic accuracy was 100%. In the NCI protocol, 23 patients underwent a telephone interview, blood test, and chest CT. Twenty patients (87%) were negative and were directly admitted to surgery. In the remaining 3 (13%), pharyngeal swab was performed. The screening was repeated until a negative chest CT was found. Diagnostic accuracy was 85%.

Conclusions: Dedicated screening protocols for COVID-19 allow to safely perform elective HNC surgery.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556777PMC
January 2021

Molecular Profiling of Salivary Oncocytic Mucoepidermoid Carcinomas Helps to Resolve Differential Diagnostic Dilemma With Low-grade Oncocytic Lesions.

Am J Surg Pathol 2020 12;44(12):1612-1622

Institute of Biomedicine, University of Turku.

Oncocytic mucoepidermoid carcinoma (OMEC) is a rare but diagnostically challenging variant of mucoepidermoid carcinoma (MEC). OMEC is notable for differential diagnostic considerations that are raised as a result of overlap with other benign and low-grade oncocytic salivary gland tumors. Diffuse and strong immunoreactivity of p63 protein may be useful in distinguishing OMEC from its mimics. However, focal p63 staining can be present in benign oncytomas. Presence of mucin-containing cells, mucinous cystic formation, and foci of extravasated mucin are considered a hallmark of MEC. True mucocytes may be, however, very few and hardly discernable in OMECs. Recent evidence has shown that most MECs harbor gene fusions involving MAML2. A retrospective review of archived pathology files and the authors' own files was conducted to search for "low-grade/uncertain oncocytic tumor," "oncocytoma," and "oncocytic carcinoma" in the period from 1996 to 2019. The tumors with IHC positivity for p63 and/or p40, and S100 negativity, irrespective of mucicarmine staining, were tested by next-generation sequencing using fusion-detecting panels to detect MAML2 gene rearrangements. Two index cases from consultation practice (A.S. and A.A.) of purely oncocytic low-grade neoplasms without discernible mucinous cells showed a CRTC1-MAML2 fusion using next-generation sequencing, and were reclassified as OMEC. In total, 22 cases of oncocytic tumors, retrieved from the authors' files, and from the Salivary Gland Tumor Registry, harbored the MAML2 gene rearrangements. Presence of mucocytes, the patterns of p63 and SOX10 immunopositivity, and mucicarmine staining were inconsistent findings. Distinguishing OMEC devoid of true mucinous cells from oncocytoma can be very challenging, but it is critical for proper clinical management. Diffuse and strong positivity for p63 and visualization of hidden mucocytes by mucicarmine staining may be misleading and does not always suffice for correct diagnosis. Our experience suggests that ancillary studies for the detection of MAML2 rearrangement may provide useful evidence in difficult cases.
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http://dx.doi.org/10.1097/PAS.0000000000001590DOI Listing
December 2020

Temporal bone carcinoma: Novel prognostic score based on clinical and histological features.

Head Neck 2020 12 27;42(12):3693-3701. Epub 2020 Aug 27.

Department of Neuroscience DNS, Otolaryngology Section, Padova University, Padova, Italy.

Background: This study aimed to develop a novel temporal bone squamous cell carcinoma (TBSCC) prognosis scoring system and compare it with the revised Pittsburgh staging system.

Methods: Forty-four consecutive TBSCC patients were assessed to identify predictors of recurrence. Each predictor's hazard ratio for recurrence was used to develop our novel scoring system.

Results: Based on variables with P < .10 in Cox's regression model, our score included: revised Pittsburgh stage; non-anterior spread of T4 carcinoma; dural involvement; and histological grade. A higher recurrence rate (P = .000) and shorter disease-free survival (P = .000) were associated with scores of ≥5. The area under the curve of our score was larger than that of the revised Pittsburgh stage for both recurrence and disease-specific mortality (P = .0178 and P = .0193, respectively).

Conclusion: Our TBSCC scoring system is based on variables that are obtainable preoperatively from clinical and radiological data and biopsies. Its prognostic value should be validated for published TBSCC series and then in prospective settings.
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http://dx.doi.org/10.1002/hed.26435DOI Listing
December 2020

Diagnostic Accuracy of Narrow Band Imaging in Patients with Oral Lichen Planus: A Prospective Study.

Laryngoscope 2021 04 14;131(4):E1156-E1161. Epub 2020 Aug 14.

Section of Otorhinolaryngology-Head and Neck Surgery, Department of Neurosciences, University of Padua, Padua, Italy.

Objective: Oral lichen planus (OLP) is a chronic mucocutaneous immune-mediated disease affecting 1% to 4% of the worldwide population. Development of malignant lesions is reported but only affects a minority of patients. The aim of our study was to assess the diagnostic potential of narrow band imaging (NBI) in OLP patients; focusing on the identification of high-grade dysplasia/carcinoma in newly developed lesions.

Methods: Prospective evaluation of 56 patients with histopathologic diagnosis of OLP and presenting newly developed lesions not responding to medical treatment. All lesions were assessed by high-definition (HD) white light (WL) and HD-NBI endoscopy. All patients underwent biopsy regardless of the appearance at HD-WL and HD-NBI. Histology was defined as "positive" in case of high-grade dysplasia or carcinoma.

Results: Five lesions (9%) were diagnosed as high-grade dysplasia/carcinoma. In this setting, overall diagnostic potential of HD-NBI was optimal, with a sensitivity of 100% (95% CI, 48-100), specificity of 96% (95% CI, 86-99), negative predictive value of 100% (95% CI, not calculable), positive predictive value of 71% (95% CI, 39-91), and accuracy of 96% (95% CI, 88-100).

Conclusions: Despite the diffuse inflammatory pattern derived from OLP, NBI improved the diagnostic accuracy and the capability to detect high-grade dysplasia/carcinoma.

Level Of Evidence: 4 Laryngoscope, 131:E1156-E1161, 2021.
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http://dx.doi.org/10.1002/lary.29035DOI Listing
April 2021

Laryngeal Compartmentalization Does Not Affect the Prognosis of T3-T4 Laryngeal Cancer Treated by Upfront Total Laryngectomy.

Cancers (Basel) 2020 Aug 11;12(8). Epub 2020 Aug 11.

IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy.

A picture is emerging in which advanced laryngeal cancers (LCs) are potentially not homogeneous and may be characterized by subpopulations which, if identified, could allow selection of patients amenable to organ preservation treatments in contrast to those to be treated with total laryngectomy (TL). This work aims to analyze a multicentric cohort of T3-T4a LCs treated by upfront TL, investigating the clinical and pathological features that can best predict oncologic outcomes. A total of 149 previously untreated patients who underwent TL for T3-T4a LC at four institutions were analyzed. Survival and disease-control were considered as the main outcomes. A secondary end-point was the identification of covariates associated with nodal status, investigating also the tumor thickness. T and N categories were significantly associated with both overall and disease-specific survival. The number of positive nodes and tracheal involvement were associated with loco-regional failure; post-cricoid area invasion and extra-nodal extension with distant failure. Posterior laryngeal compartment involvement was not a significant prognostic feature, by either univariable and multivariable analyses. These results support the conclusion that laryngeal compartmentalization has no impact on survival in patients treated by upfront TL and the current TNM staging system remains a robust prognosticator in advanced LC.
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http://dx.doi.org/10.3390/cancers12082241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463701PMC
August 2020