Circulating tumor HPV DNA in the management of HPV+ oropharyngeal cancer and its correlation with MRI.

BACKGROUND: First aim was to compare ddPCR assays of ctHPVDNA with p16 IHC and qualitative HPV PCR. Second aim was to carry out longitudinal blood sampling to test for association of ctHPVDNA with histological confirmed recurrence. Third aim was to perform a multidimensional assessment which included: (1) clinical features; (2) ctHPVDNA; (3) MRI-based tumor size measurements of primary tumor (PT) and cervical lymph node metastases (CLNM). METHODS: Plasma samples were collected before treatment and during follow-up, and ddPCR assay comprising E6 of HPV16 and HPV 33 and HPV 35 was used. RESULTS: Present study was conducted at diagnosis in 117 patients and revealed a ctHPVDNA sensitivity of 100% (95% CI 95.5-100) and a specificity of 94.4 (95% CI 81.3-99.3), positive predictive value (PPV) of 94.4 (95% CI 81.3-99.3), and negative predictive value (NPP) of 100% (95% CI 89.7-100). During follow-up ctHPVDNA had a sensitivity of 100% (95% CI 72.1-100)% and specificity of 98.4% (95% CI 91.7-100)%, PPV% of 90.9% (95% CI 62.3-98.4) and NPV% of 100% (95% CI 94.3-100) for ability to detect recurrence. Correlation between both the CLNM volume and the sum of PT and CLNM volume was observed. CONCLUSIONS: ctHPVDNA was superior to p16 in identification of HPV-OPSCC at diagnosis. Introduction of ctHPVDNA, beyond diagnostic setting, represents a great opportunity to improve follow-up protocol of OPSCC patients.

A multicenter protocol to assess the prognostic significance of the tumor microenvironment in patients with squamous cell carcinoma of the larynx.

BACKGROUND: The purpose of this multicenter study was to retrospectively investigate the prognostic significance of the tumor microenvironment, in relation to survival in a large cohort of patients with laryngeal squamous cell carcinoma (LSCC), using the method proposed by the International TILs Working Group in breast cancer. METHODS: All consecutive patients with biopsy-proven LSCC who underwent total laryngectomy (TL) between January 2014 and January 2023 were retrospectively included in the study. A retrospective review of medical records including surgical, pathological and follow-up reports was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group. RESULTS: The study group included 186 patients with LSCC. High TILs were statistically correlated with reduced size and extension of primary tumor (pT stage) with a statistically significant value (S: p = 0.01; P: p = 0.0003) and without needs of salvage therapy (S: p = 0.03; P: p = 0.004). Low TILs were indicative of worse prognosis. CONCLUSIONS: Our study confirmed the protective value of TILs and the prognostic role of the tumor microenvironment in LSCC; furthermore, our results showed that the score proposed by the International TILs Working Group for breast cancer can be applied to LSCC.

Role of Tumor-Infiltrating Lymphocytes and the Tumor Microenvironment in the Survival of Malignant Parotid Gland Tumors: A Two-Centre Retrospective Analysis of 107 Patients.

Background: This study aims to retrospectively investigate the prognostic significance of the tumor microenvironment, with a focus on TILs (tumor-infiltrating lymphocytes), in relation to survival in a large cohort of patients with parotid gland cancer, and it uses the method proposed by the International TILs Working Group in breast cancer. Methods: We included a cohort of consecutive patients with biopsy-proven parotid cancer who underwent surgery between January 2010 and September 2023. A retrospective review of medical records, including surgical, pathological and follow-up reports, was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group for breast cancer. Results: A weak negative correlation (p = 0.3) between TILs and time of survival and a weak positive correlation (p = 0.05) between TILs and months of survival (high TILs were correlated with longer survival in months) were identified. High TILs were weakly negatively, but not statistically significantly p (0.7), correlated with the grading of tumor; this means that high TILs were associated with low-grade tumors. Conclusions: Contrary to previous preliminary reports, this retrospective work found no statistically significant prognostic role of TILs in parotid gland malignancies. This case series represents the largest cohort ever reported in the literature and includes all malignant histological types. Future larger molecular studies may be useful in this regard.

Combined TP53 status in tumor-free resection margins and circulating microRNA profiling predicts the risk of locoregional recurrence in head and neck cancer.

Locoregional recurrences represent a frequently unexpected problem in head and neck squamous cell carcinoma (HNSCC). Relapse often (10-30%) occurs in patients with histologically negative resection margins (RMs), probably due to residual tumor cells or hidden pre-cancerous lesions in normal mucosa, both missed by histopathological examination. Therefore, definition of a 'clean' or tumor-negative RM is controversial, demanding for novel approaches to be accurately explored. Here, we evaluated next generation sequencing (NGS) and digital PCR (dPCR) as tools to profile TP53 mutational status and circulating microRNA expression aiming at scoring the locoregional risk of recurrence by means of molecular analyses. Serial monitoring of these biomarkers allowed identifying patients at high risk, laying the ground for accurate tracking of disease evolution and potential intensification of post-operative treatments. Additionally, our pipeline demonstrated its applicability into the clinical routine, being cost-effective and feasible in terms of patient sampling, holding promise to accurately (re)-stage RMs in the era of precision medicine.

Management of nasal vestibule carcinomas: recommendations by the Oncological Committee of the Italian Society of Otorhinolaryngology - Head and Neck Surgery.

Objective: Squamous cell carcinoma of the nasal vestibule (NV SCC) is a head and neck malignancy for which there is no established consensus on most aspects of clinical management. The purpose of this document is to give updated recommendations that incorporate recent evidence on its clinical characteristics and the high efficacy of brachytherapy as primary treatment modality. Methods: A working group consisting of the members of the Scientific Committee for Oncology and Reconstructive Surgery of the Italian Society of Otorhinolaryngology Head and Neck Surgery and radiation oncologists expert in brachytherapy was formed to achieve a consensus. Results: Consensus was reached on a set of recommendations, proposing a refined anatomical definition of the nasal vestibule, a novel T staging system of the NV SCC, and brachytherapy as standard of care, with a new method for catheter implantation. Conclusions: The Committee emphasises the critical role of an accurate classification in clinical practice and encourages further research to validate the novel staging system and further improve treatment strategies. Where appropriate, it is recommended that patients be referred to centres with specific experience in brachytherapy for NV SCC.

Impact of Adjuvant Radiotherapy in Squamous Cell Carcinoma of the Oral Cavity with Perineural Invasion.

OBJECTIVE: Current guidelines indicate postoperative radiotherapy (PORT) in oral squamous cell carcinoma (OSCC) with perineural invasion (PNI), however, its real benefit has never been proven. The aim of our study is to investigate the benefit of PORT in OSCC patients with PNI in terms of survival and disease control. DATA SOURCES: The Pubmed/MEDLINE, Cochrane Library, and Scopus databases. REVIEW METHODS: Patients with PNI + OSCC treated with primary surgery were extracted from the included studies. The pooled logHR was calculated by comparing patients who underwent PORT to those who underwent only observation for overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and locoregional control (LRC). RESULTS: About 690 patients with primary OSCC and PNI were included from nine studies. 374 (54.2%) patients underwent PORT, while 316 (45.8%) underwent observation. Analyses showed non-significant difference between the two groups for OS (HR: 1.01; 95% CI: 0.38-2.69), DSS (HR: 2.03; 95% CI: 0.54-7.56), and LRC (HR: 0.89; 95% CI: 0.53-1.50). They showed a significant difference in terms of DFS (HR: 0.86; 95% CI: 0.77-0.97). CONCLUSION: The real benefit of PORT in OSCC patients with PNI is still unclear, although it may have a positive impact on DFS. Clinicians should consider individual patient's characteristics, tumor factors, and treatment goals when deciding whether to recommend PORT. Further studies are needed to clarify which entity of PNI really benefits from PORT. LEVEL OF EVIDENCE: NA Laryngoscope, 134:2019-2027, 2024.

A Retrospective Multicenter Italian Analysis of Epidemiological, Clinical and Histopathological Features in a Sample of Patients with Acinic Cell Carcinoma of the Parotid Gland.

BACKGROUND: The acinic cell carcinoma (AciCC) of the parotid gland is a rare tumor with an indolent behavior; however, a subgroup of this tumor presents an aggressive behavior with a tendency to recur. The aim of this multicenter study was to identify and stratify those patients with AciCC at high risk of tumor recurrence. METHODS: A retrospective study was carried out involving 77 patients treated with surgery between January 2000 and September 2022, in different Italian referral centers. Data about tumor characteristics and its recurrence were collected. The histological specimens and slides were independently reviewed by a senior pathologist coordinator (L.C.) and the institution's local head and neck pathologist. RESULTS: The patients' age average was 53.6 years, with a female prevalence in the group. The mean follow-up was 67.4 months (1-258, SD 59.39). The five-year overall survival (OS) was 83.2%. The 5-year disease-free survival (DFS) was 60% (95% CI 58.2-61.7). A high incidence of necrosis, extraglandular spread, lymphovascular invasion (LVI), atypical mitosis, and cellular pleomorphism was observed in the high-risk tumors compared to the low-risk ones. CONCLUSION: AciCC generally had an indolent behavior, optimal OS, DFS with few cervical node metastases, and rare distant relapses. This multicenter retrospective case series provides evidence of the need for clinical-epidemiological-histological stratification for patients at risk of poor outcomes. Our results suggest that the correct definition of high-risk AciCC should include tumor size, the presence of necrosis, extraglandular spread, LVI, atypical mitosis, and cellular pleomorphism.

Immunosignatures associated with TP53 status and co-mutations classify prognostically head and neck cancer patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a therapeutic strategy for various cancers although only a subset of patients respond to the therapy. Identifying patients more prone to respond to ICIs may increase the therapeutic benefit and allow studying new approaches for resistant patients. METHODS: We analyzed the TCGA cohort of HNSCC patients in relation to their activation of 26 immune gene expression signatures, as well as their cell type composition, in order to define signaling pathways associated with resistance to ICIs. Results were validated on two cohorts of 102 HNSCC patients and 139 HNSCC patients under treatment with PD-L1 inhibitors, respectively, and a cohort of 108 HNSCC HPV negative patients and by in vitro experiments in HNSCC cell lines. RESULTS: We observed a significant association between the gene set and TP53 gene status and OS and PFS of HNSCC patients. Surprisingly, the presence of a TP53 mutation together with another co-driver mutation was associated with significantly higher levels of the immune gene expression, in comparison to tumors in which the TP53 gene was mutated alone. In addition, the higher level of TP53 mutated-dependent MYC signature was associated with lower levels of the immune gene expression signature. In vitro and three different patient cohorts validation analyses corroborated these findings. CONCLUSIONS: Immune gene signature sets associated with TP53 status and co-mutations classify with more accuracy HNSCC patients. These biomarkers may be easily implemented in clinical setting.

It is time to improve the diagnostic workup of oropharyngeal cancer with circulating tumor HPV DNA: Systematic review and meta-analysis.

The possibility of detecting circulating tumor HPV DNA (ctHPVDNA) in plasma in patients with oropharyngeal cancer has been demonstrated in several reports. However, these data are from small cohorts and available tests for detection of ctHPVDNA are not fully validated. The aim is to evaluate sensitivity, specificity, and accuracy of ctHPVDNA by ddPCR to define its efficacy in the clinical setting for the diagnosis of HPV + OPSCC. A comprehensive search of three different databases: MEDLINE, Embase, and Cochrane Library databases. A total of 998 patients were evaluated from the 13 studies. OPSSC p16+ were 729, while controls p16- were 269. The meta-analytic study estimated the diagnostic performance of ctHPVDNA as follows: pooled sensitivity and specificity of 0.90 (95% CI: 0.82-0.94) and 0.94 (95% CI: 0.85-0.98), respectively; positive and negative likelihood ratios of 12.6 (95% CI: 4.9-32.1) and 0.05 (95% CI: 0.02-0.13), respectively. ddPCR for ctHPVDNA has good accuracy, sensitivity, and specificity for diagnosis of HPV + OPSCC. ctHPVDNA kinetic represents a great reliable opportunity to improve diagnostic and therapeutic management of cancer patients and could open new perspectives for understanding tumor biology.

Magnetic resonance imaging-based prediction models for tumor stage and cervical lymph node metastasis of tongue squamous cell carcinoma.

Purpose: To evaluate the ability of preoperative MRI-based measurements to predict the pathological T (pT) stage and cervical lymph node metastasis (CLNM) via machine learning (ML)-driven models trained in oral tongue squamous cell carcinoma (OTSCC). Materials and methods: 108 patients with a new diagnosis of OTSCC were enrolled. The preoperative MRI study included post-contrast high-resolution T1-weighted images acquired in all patients. MRI-based depth of invasion (DOI) and tumor dimension-together with shape-based and intensity-based features-were extracted from the lesion volume segmentation. The entire dataset was randomly divided into a training set and a validation set, and the performances of different types of ML algorithms were evaluated and compared. Results: MRI-based DOI and tumor dimension together with several shape-based and intensity-based signatures significantly discriminated the pT stage and LN status. The overall accuracy of the model for predicting the pT stage was 0.86 (95%CI, 0.78-0.92) and 0.81 (0.64-0.91) in the training and validation sets, respectively. There was no improvement in the model performance upon including shape-based and intensity-based features. The model for predicting CLNM based on DOI and tumor dimensions had a fair accuracy of 0.68 (0.57-0.78) and 0.69 (0.51-0.84) in the training and validation sets, respectively. The shape-based and intensity-based signatures have shown potential for improving the model sensitivity, with a comparable accuracy. Conclusion: MRI-based models driven by ML algorithms could stratify patients with OTSCC according to the pT stages. They had a moderate ability to predict cervical lymph node metastasis.

Second primary carcinoma arising on a flap: a new primary or a relapse?

BACKGROUND AND AIM: Free flaps or pedicle flaps are the mainstay of cancer surgery in the head and neck area. However, their long-term sequelae are still poorly understood. Among these, the development of a secondary primary tumor on a flap is a rare and uncertain reported event.   Methods: A computer-aided systematic literature search was performed by using the PubMed, EMBASE and Cochrane Library databases. A systematic review of the literature, following the PRISMA checklist, was carried out with the aim of analyzing all the citations reporting this second primary, with attention to risk factors, behavior, etiological causes.   Results: Overall, 27 cases of second primary squamous cell carcinoma arising on a pedicle or free flap were identified. In addition, other three cases were discussed.   Conclusions: Persistent exposure to oral stimuli such saliva, oral microbiome, smoke or a colonization by the adjacent mucosa were considered as a possible cause of second primary carcinoma. Although rare, a new neoplasm onset should know and considered as a new concept in the follow-up of patients undergoing reconstruction with free or pedicle flaps.

Impact of lymph node ratio and number of lymph node metastases on survival and recurrence in laryngeal squamous cell carcinoma.

INTRODUCTION: The aim of this study is to assess the impact of lymph node ratio (LNR) and number of positive lymph nodes (NPLN) on mortality and recurrence rates in patients with laryngeal squamous cell carcinoma. MATERIALS AND METHODS: We conducted a retrospective multicenter international study involving 24 Otorhinolaryngology-Head and Neck Surgery divisions. Disease-specific survival (DSS) and disease-free survival (DFS) were evaluated as the main outcomes. The curves for DSS and DFS according to NPLN and LNR were analyzed to identify significant variations and establish specific cut-off values. RESULTS: 2507 patients met the inclusion criteria. DSS and DFS were significantly different in the groups of patients stratified according to LNR and NPLN. The 5-year DSS and DFS based on LNR and NPLN demonstrated an improved ability to stratify patients when compared to pN staging. CONCLUSION: Our data demonstrate the potential prognostic value of NPLN and LNR in laryngeal squamous cell carcinoma.

Machine learning in laryngeal cancer: A pilot study to predict oncological outcomes and the role of adverse features.

BACKGROUND: Laryngeal carcinoma (LC) remains a significant economic and emotional problem to the healthcare system and severe social morbidity. New tools as Machine Learning could allow clinicians to develop accurate and reproducible treatments. METHODS: This study aims to evaluate the performance of a ML-algorithm in predicting 1- and 3-year overall survival (OS) in a cohort of patients surgical treated for LC. Moreover, the impact of different adverse features on prognosis will be investigated. Data was collected on oncological FU of 132 patients. A retrospective review was performed to create a dataset of 23 variables for each patient. RESULTS: The decision-tree algorithm is highly effective in predicting the prognosis, with a 95% accuracy in predicting the 1-year survival and 82.5% in 3-year survival; The measured AUC area is 0.886 at 1-year Test and 0.871 at 3-years Test. The measured AUC area is 0.917 at 1-year Training set and 0.964 at 3-years Training set. Factors that affected 1yOS are: LNR, type of surgery, and subsite. The most significant variables at 3yOS are: number of metastasis, perineural invasion and Grading. CONCLUSIONS: The integration of ML in medical practices could revolutionize our approach on cancer pathology.

Submandibular gland involvement in oral cavity squamous cell carcinoma: a retrospective multicenter study.

BACKGROUND: The submandibular gland (SMG) is routinely excised during neck dissection. Given the importance of the SMG in saliva production, it is important to understand its involvement rate by cancer tissue and the feasibility of its preservation. METHODS: Retrospective data were collected from five academic centers in Europe. The study involved adult patients affected by primary oral cavity carcinoma (OCC) undergoing tumor excision and neck dissection. The main outcome analyzed was the SMG involvement rate. A systematic review and a meta-analysis were also conducted to provide an updated synthesis of the topic. RESULTS: A total of 642 patients were enrolled. The SMG involvement rate was 12/642 (1.9%; 95% CI 1.0-3.2) when considered per patient, and 12/852 (1.4%; 95% CI 0.6-2.1) when considered per gland. All the glands involved were ipsilateral to the tumor. Statistical analysis showed that predictive factors for gland invasion were: advanced pT status, advanced nodal involvement, presence of extracapsular spread and perivascular invasion. The involvement of level I lymph nodes was associated with gland invasion in 9 out of 12 cases. pN0 cases were correlated with a reduced risk of SMG involvement. The review of the literature and the meta-analysis confirmed the rare involvement of the SMG: on the 4458 patients and 5037 glands analyzed, the involvement rate was 1.8% (99% CI 1.1-2.7) and 1.6% (99% CI 1.0-2.4), respectively. CONCLUSIONS: The incidence of SMG involvement in primary OCC is rare. Therefore, exploring gland preservation as an option in selected cases would be reasonable. Future prospective studies are needed to investigate the oncological safety and the real impact on quality of life of SMG preservation.

Trans oral robotic surgery for oropharyngeal cancer: A multi institutional experience.

OBJECTIVES: Trans Oral Robotic Surgery (TORS) has proved to be a safe and feasible treatment for oropharyngeal squamous cell carcinoma (OPSCC). The aim of this study is to analyse oncological outcomes of OPSCC patients treated with TORS. MATERIALS AND METHODS: This study involved 139 patients with OPSCC, treated with TORS between 2008 and 2020. Clinicopathological characteristics, treatment details and oncological outcomes were evaluated retrospectively. RESULTS: The management strategies included TORS alone in 42.5%, TORS-RT in 25.2% and TORS-CRT in 30.9%. The ENE was noted in 28.8% of neck dissections. In 19 patients clinically classified as unknown primaries, the primary was found in 73.7%. Rates of local, regional relapses and distant metastasis were 8.6%, 7.2%, and 6.5%, respectively. The 5 year- Overall Survival and Disease Free Survival were 69.6% and 71.3%, respectively. CONCLUSION: TORS fits well in the modern management of OPSCC. Although definitive CRT remains a milestone, TORS is proving to be a valid and safe treatment option. The choice of the therapeutic strategy requires evaluation by a multidisciplinary team.

Transoral Laser Microsurgery in Recurrent Laryngeal Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To determine the oncological outcomes of salvage transoral laser microsurgery (TLM) in the treatment of patients suffering from recurrent laryngeal cancer. METHODS: PubMed/MEDLINE, Cochrane Library, and Scopus databases were searched. English language, original studies investigating oncological outcomes of TLM in adult patients with recurrent laryngeal cancer were included. Data were pooled using a distribution-free approach for estimating summary local control (LC), disease-specific survival (DSS), and overall survival (OS) curves with random effects. RESULTS: Two hundred and thirty-five patients underwent salvage TLM after primary (chemo)radiotherapy. The mean follow-up time was 60.8 months (95% CI: 32.7-88.9). Estimated pooled LC rates (95% CI) at 1, 3 and 5 years were 74.2% (61.7-89.4), 53.9% (38.5-75.3), and 39.1% (25.2-60.8). Estimated pooled DSS rates (95% CI) at 1, 3 and 5 years were 88.4% (82.0-95.3), 67.8% (50.9-90.3), and 58.9% (42.7-81.1). Two hundred and seventy-one patients underwent TLM after primary laser treatment. The mean follow-up time was 70.9 months (95% CI: 36.9-104.9). Estimated pooled LC rates (95% CI) at 1, 3 and 5 years were 72.2% (64.7-80.6), 53.2% (42.2-66.9), and 40.4% (29.6-55.2). Estimated pooled DSS rates (95% CI) at 1, 3 and 5 years were 92.1% (85.5-99.1), 77.0% (64.4-92.0), and 67.1% (51.6-87.3). CONCLUSIONS: TLM is a valuable treatment option for the management of locally recurrent laryngeal carcinoma if performed by experienced surgeons and following rigorous patients' selection criteria. Further studies should be conducted to define stage-based clinical guidelines. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1425-1433, 2023.

Treatment of oropharyngeal squamous cell carcinoma: Is swallowing quality better after TORS or RT?

BACKGROUND AND PURPOSE: To answer an important question regarding the long-term morbidity of two oncological equivalent treatment for oropharyngeal squamous cell carcinoma (OPSCC), namely a comparison of swallowing function results between patients treated with trans-oral robotic surgery (TORS) versus patients treated with radiotherapy (RT). MATERIALS AND METHODS: Studies included patients with OPSCC treated with TORS or RT. Articles reporting complete data on MD Anderson Dysphagia Inventory (MDADI) and comparing the two treatments (TORS vs RT) were included in the meta-analysis. Swallowing assessed with MDADI was the primary outcome, the evaluation with instrumental methods was the secondary aim. RESULTS: Included studies provided a total of 196 OPSCC primarily treated with TORS vs 283 OPSCC primarily treated with RT. The mean difference in MDADI score at the longest follow-up was not significantly different between TORS and RT group (mean difference [MD] -0.52; 95% CI -4.53-3.48; p = 0.80). After treatment, mean composite MDADI scores demonstrated a slight impairment in both groups without reaching a statistical difference compared to the baseline status. DIGEST score and Yale score showed a significantly worse function in both treatment groups at 12-month follow-up compared to baseline status. CONCLUSION: The meta-analysis demonstrates that up-front TORS (+- adjuvant therapy) and up-front RT (+- CT) appear to be equivalent treatments in functional outcomes in T1-T2, N0-2 OPSCC, however, both treatments cause impaired swallowing ability. Clinicians should have a holistic approach and work with patients to develop an individualized nutrition plan and swallowing rehabilitation protocol from diagnosis to post-treatment surveillance.