Defining the Genomic Landscape of Diffuse Sclerosing Papillary Thyroid Carcinoma: Prognostic Implications of RET Fusions.

BACKGROUND: Diffuse sclerosing papillary thyroid carcinoma (DSPTC) is an aggressive histopathologic subtype of papillary thyroid carcinoma. Correlation between genotype and phenotype has not been comprehensively described. This study aimed to describe the genomic landscape of DSPTC comprehensively using next-generation sequencing (NGS), analyze the prognostic implications of different mutations, and identify potential molecular treatment targets. METHODS: Tumor tissue was available for 41 DSPTC patients treated at Memorial Sloan Kettering Cancer Center between 2004 and 2021. After DNA extraction, NGS was performed using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform, which sequences 505 critical cancer genes. Clinicopathologic characteristics were compared using the chi-square test. The Kaplan-Meier method and log-rank statistics were used to compare outcomes. RESULTS: The most common mutation was RET fusion, occurring in 32% (13/41) of the patients. Other oncologic drivers occurred in 68% (28/41) of the patients, including 8 BRAFV600E mutations (20%) and 4 USP8 mutations (10%), which have not been described in thyroid malignancy previously. Patients experienced RET fusion-positive tumors at a younger age than other drivers, with more aggressive histopathologic features and more advanced T stage (p = 0.019). Patients who were RET fusion-positive had a significantly poorer 5-year recurrence-free survival probability than those with other drivers (46% vs 84%; p = 0.003; median follow-up period, 45 months). In multivariable analysis, RET fusion was the only independent risk factor for recurrence (hazard ratio [HR], 7.69; p = 0.017). CONCLUSION: Gene-sequencing should be strongly considered for recurrent DSPTC due to significant prognostic and treatment implications of RET fusion identification. The novel finding of USP8 mutation in DSPTC requires further investigation into its potential as a driver mutation.

Parotidectomy for deep lobe pleomorphic adenomas is associated with higher rates of complications and recurrence.

BACKGROUND: Pleomorphic adenoma (PA) is a common parotid tumor, yet due to the relative rarity of deep lobe PA (DLPA), there is a paucity of information about its clinical presentation and surgical outcomes. METHODS: We reviewed the charts of patients with previously untreated parotid PA between the years 1990 and 2015. Clinical parameters and surgical outcomes were compared between superficial lobe PA (SLPA) and DLPA. RESULTS: The cohort comprised 147 cases of DLPA and 222 cases of SLPA. DLPA were larger (median 2.6 cm vs. 2.0 cm, p < 0.001), more often discovered incidentally on imaging (33%, n = 48) and had unique presentations (pharyngeal mass, dysphagia, otalgia). Postsurgical complications were more frequently observed in DLPA (41% vs. 30% in SLPA, p = 0.025), mainly transient facial nerve weakness. DLPA also showed higher recurrence rates (n = 6, 4.1% vs. n = 1, 0.4%, p = 0.016). CONCLUSIONS: Parotidectomy for DLPA carries a higher risk of complications and recurrence compared to SLPA.

Skull base surgery for malignant tumors: The 2nd international collaborative study (1995-2015).

BACKGROUND: The current study presents the effort of a global collaborative group to review the management and outcomes of malignant tumors of the skull base worldwide. PATIENTS AND METHODS: A total of 28 institutions contributed data on 3061 patients. Analysis evaluated clinical variables, survival outcomes, and multivariable factors associated with outcomes. RESULTS: The median age was 56 years (IQR 44-67). The open surgical approach was used in 55% (n = 1680) of cases, endoscopic resection was performed in 36% (n = 1087), and the combined approach in 9.6% (n = 294). With a median follow-up of 7.1 years, the 5-year OS DSS and RFS were 65%, 71.7% and 53%, respectively. On multivariable analysis, older age, comorbidities, histology, dural/intracranial involvement, positive margins, advanced stage, and primary site were independent prognostic factors for OS, DSS, and RFS. Adjuvant RT was a protective prognostic factor. CONCLUSION: The progress across various disciplines may have contributed to improved OS and DSS in this study compared to previous reports.

Outcomes of Conversion Surgery for Patients With Low-Risk Papillary Thyroid Carcinoma.

Importance: The outcomes of patients with low-risk thyroid cancer who undergo surgery following a period of active surveillance (AS) are not well-defined. Objective: To evaluate surgical, pathologic, and oncologic outcomes among patients undergoing conversion surgery (CS) following AS for low-risk papillary thyroid carcinoma. Design, Setting, and Participants: In this cohort study, patients who underwent CS for disease progression were compared with patients who underwent CS without disease progression and with a propensity score-matched cohort of patients who underwent initial surgery (IS). The median (IQR) postsurgical follow-up time was 40.3 (18.0-59.0) months. Patients were treated at a quaternary cancer referral center in the United States. Exposures: Surgery. Main Outcomes and Measures: Surgical complications, pathologic characteristics, overall survival (OS), and recurrence-free survival (RFS). Results: Of 550 patients who underwent AS, 55 (10.0%) had CS, of whom 39 (7.1%) had surgery due to suspected disease progression (median [IQR] age, 48 [39-56] years; 32 [82.1%] female). There were no clinically meaningful differences in rates of surgical sequalae between the progression CS group (12 of 39 [30.7%]) and the nonprogression CS group (7 of 16 [43.8%]) (Cramer V, 0.2; 95% CI, 0.01-0.5). The 5-year OS was 100% (95% CI, 100%-100%) in both the disease-progression CS cohort and the IS cohort. Although the cohort of patients undergoing CS after disease progression was by definition a subset with more aggressive tumor behavior, no clinically meaningful differences were observed in the rates of regional recurrence (2 of 39 [5.1%] vs 0 of 39 patients with IS), local recurrence (0 patients), distant metastasis (0 patients), or disease-specific mortality (0 patients) when compared with the matched IS group. Five-year RFS rates were similar: 100% in the IS group and 86% (95% CI, 70%-100%) in the CS group. Conclusions and Relevance: In this cohort study, CS for suspected disease progression was associated with surgical and oncologic outcomes similar to IS, supporting the feasibility and safety of AS for patients with low-risk papillary thyroid carcinoma.

Recurrent Laryngeal Nerve Intraoperative Neuromonitoring Indications in Non-Thyroid and Non-Parathyroid Surgery.

Introperative nerve monitoring (IONM) of the recurrent laryngeal nerve (RLN) is a well-established technique to aid in thyroid/parathyroid surgery. However, there is little evidence to support its use in non-thyroid or non-parathyroid surgery. The aim of this paper was to review the current evidence regarding the use of IONM in non-thyroid/non-parathyroid surgery in the head and neck and thorax. A literature search was performed from their inception up to January 2024, including the term "recurrent laryngeal nerve monitoring". IONM in non-thyroid/non-parathyroid surgery has mainly been previously described in oesophageal surgery and in tracheal resections. However, there is little published evidence on the role of IONM with other resections in the vicinity of the RLN. Current evidence is low-level for the use of RLN IONM in non-thyroid/non-parathyroid surgery. However, clinicians should consider its use in surgery for pathologies where the RLN is exposed and could be injured.

Hypoxia-Directed Treatment of Human Papillomavirus-Related Oropharyngeal Carcinoma.

PURPOSE: Standard curative-intent chemoradiotherapy for human papillomavirus (HPV)-related oropharyngeal carcinoma results in significant toxicity. Since hypoxic tumors are radioresistant, we posited that the aerobic state of a tumor could identify patients eligible for de-escalation of chemoradiotherapy while maintaining treatment efficacy. METHODS: We enrolled patients with HPV-related oropharyngeal carcinoma to receive de-escalated definitive chemoradiotherapy in a phase II study (ClinicalTrials.gov identifier: NCT03323463). Patients first underwent surgical removal of disease at their primary site, but not of gross disease in the neck. A baseline 18F-fluoromisonidazole positron emission tomography scan was used to measure tumor hypoxia and was repeated 1-2 weeks intratreatment. Patients with nonhypoxic tumors received 30 Gy (3 weeks) with chemotherapy, whereas those with hypoxic tumors received standard chemoradiotherapy to 70 Gy (7 weeks). The primary objective was achieving a 2-year locoregional control (LRC) of 95% with a 7% noninferiority margin. RESULTS: One hundred fifty-eight patients with T0-2/N1-N2c were enrolled, of which 152 patients were eligible for analyses. Of these, 128 patients met criteria for 30 Gy and 24 patients received 70 Gy. The 2-year LRC was 94.7% (95% CI, 89.8 to 97.7), meeting our primary objective. With a median follow-up time of 38.3 (range, 22.1-58.4) months, the 2-year progression-free survival (PFS) and overall survival (OS) rates were 94% and 100%, respectively, for the 30-Gy cohort. The 70-Gy cohort had similar 2-year PFS and OS rates at 96% and 96%, respectively. Acute grade 3-4 adverse events were more common in 70 Gy versus 30 Gy (58.3% v 32%; P = .02). Late grade 3-4 adverse events only occurred in the 70-Gy cohort, in which 4.5% complained of late dysphagia. CONCLUSION: Tumor hypoxia is a promising approach to direct dosing of curative-intent chemoradiotherapy for HPV-related carcinomas with preserved efficacy and substantially reduced toxicity that requires further investigation.

Posttreatment complications in pediatric cervical neuroblastoma: A retrospective case series at a tertiary cancer center.

BACKGROUND: Neuroblastomas rarely occur as primary tumors in the cervical region. Therefore, very little has been reported regarding treatment strategies, complications, and outcomes of these cervical neuroblastomas. The goal of this study is to review the presentation, management, and outcomes of all primary cervical pediatric neuroblastoma cases at a single tertiary care center. METHODS: A retrospective cohort review of all neuroblastoma patients treated at a single center were performed. All patients with primary cervical neuroblastoma were reviewed for demographic information, tumor characteristics, treatment, and outcomes. RESULTS: Thirty (1.8%) patients were found to have undergone treatment for cervical neuroblastoma tumors diagnosed on average at 2.1 years old. Most presented with a swollen neck/palpable mass ± Horner's syndrome. Based on features including tumor staging, N-myc proto-oncogene protein (MYCN) amplification status, histology, most were deemed intermediate or high risk. Treatment strategies centered around chemotherapeutic regimens with surgery when possible as well as various adjuvant treatments including radiation therapy, immunotherapy, bone marrow transplant, and a neuroblastoma vaccine. Ten (33.3%) of patients experienced treatment-related complications and four (13.3%) died as a result of their disease progression. All four patients were high-risk patients, two of which had MYCN amplification. CONCLUSION: Cervical neuroblastomas generally have favorable outcomes. These tumors can be treated effectively with chemotherapy and surgical intervention with various adjuvant therapies. MYCN amplification and higher stage disease presentation contribute to worse outcomes.

Recent advances in head and neck surgical oncology.

In recent years, the field of head and neck oncology has witnessed a remarkable transformation with unprecedented advances that have revolutionized the management of complex tumors in this region. As an intricate subspecialty within oncology, head and neck surgical procedures demand detailed knowledge of the complex anatomy meticulous precision in surgical technique, and expertise to preserve vital functions while ensuring optimal oncological outcomes. With the relentless pursuit of improved patient outcomes, the integration of innovative technologies has significantly enhanced the surgical armamentarium. Robotics, endoscopic platforms, and image-guided navigation have revolutionized the surgical approach, enabling precise tumor resection and sparing healthy tissues. Furthermore, the application of advanced imaging modalities and molecular biomarker profiling has opened new avenues for personalized treatment strategies. From targeted therapies and immunotherapies to adaptive radiation techniques, clinicians are now equipped with an array of tailored options, ushering in a new era of personalized care for patients with head and neck malignancies. This article delves into the unfolding narratives of clinical triumphs, exploring the transformative potential of emerging therapies and the collaborative efforts propelling head and neck surgical oncology toward a future of hope and healing.

Risk of Carcinoma in Pleomorphic Adenomas of the Parotid.

Importance: Surgery is the mainstay of treatment for pleomorphic adenomas (PAs) of the parotid to prevent further growth and potential future malignant transformation. While historical case series have reported transformation rates as high as 10%, there is a lack of contemporary methodologically sound data. Objective: To examine the rate of carcinoma ex pleomorphic adenoma (CXPA) detection in untreated PAs and investigate factors associated with malignant neoplasm. Design, Setting, and Participants: This cohort study reviewed all cases of primary PAs managed at a quaternary referral center between December 1990 and January 2015. Patients whose clinical presentation was compatible with a primary benign PA and whose history indicated tumor duration of over 1 year were included. Data were analyzed from January to April 2023. Exposure: Untreated PA. Main Outcomes and Measures: Rate of CXPA detection among untreated PAs and association of tumor duration with rates of CXPA detection. Pathology slides of patients who underwent surgery were reviewed by a single expert pathologist for the presence of CXPA. Univariable logistic regression was performed to evaluate possible factors associated with CXPA. Results: A total of 260 patients (median age, 47 years [IQR, 38-60 years]; 174 [66.9%] female) had a median tumor duration of 3.2 years (range, 1-30 years; mean [SD], 5.7 [5.5] years). Patients were divided into 4 groups by tumor duration: 1 to 4 years (158 [60.7%]), 5 to 9 years (47 [18.1%]), 10 to 14 years (27 [10.4%]), and 15 to 30 years (28 [10.8%]). In 156 of 170 patients who underwent preoperative fine-needle aspiration (91.8%), a benign tumor was diagnosed; 5 of these patients (3.2%; 95% CI, 1.4%-7.3%) were later diagnosed with CXPA on pathology after eventual excision, and the rate of high grade CXPA was 1.3%. None of the patients had permanent facial nerve paralysis. Tumor size at presentation (odds ratio [OR], 1.66; 95% CI, 1.22-2.24) and incremental (per year) increase in age (OR, 1.04; 95% CI, 1.01-1.08) were found to be associated with CXPA, whereas tumor duration was not (OR, 1.00; 95% CI, 1.00-1.01). Conclusions and Relevance: In this study, the rate of malignant neoplasm detection among initially untreated PA was 3.2%. The results suggest that tumor size and older age are associated with the development of CXPA, while tumor duration is not. Observation of PA for longer periods was not associated with serious permanent complications.

Review of Outcomes after Salvage Surgery for Recurrent Squamous Cell Carcinoma of the Head and Neck.

Surgery with adjuvant chemoradiotherapy or chemoradiotherapy is the mainstay in treatment for advanced stage head and neck squamous cell carcinoma; however, locoregional recurrences are frequent. Salvage surgery could be proposed in selected patients to improve local control, disease-free, and overall survival. Factors for improved disease-free and overall survival in patients treated with salvage surgery include age, tumor location, the initial T stage, HPV status, resection margins, and the time elapsing from the initial treatment. Clinical trials with adjuvant therapies have shown promise after salvage surgery in terms of tolerance and response, but clinical guidelines for using these adjuvant treatments are currently lacking. The aim of this review is to present current knowledge concerning the incidence and management of recurrent head and neck squamous cell carcinoma and current data concerning survival and morbidity after salvage surgery.

CAD/CAM-assisted ablative surgery and intraoperative brachytherapy for pediatric skull-base sarcomas.

BACKGROUND: Head and neck (H&N) sarcomas in children can poise numerous challenges to the surgical oncologist and require multidisciplinary input and meticulous surgical planning. The application of computer-assisted design/computer-assisted manufacturing (CAD/CAM) has been extensively examined in H&N reconstruction in adults, but its utility in ablative oncologic surgery in children warrants further examination. We present preliminary results utilizing CAD/CAM techniques to assist in planning tumor resections and the application of intra-operative radiation in children with skull-base sarcomas. METHODS: A retrospective cohort review of all pediatric patients who presented to a tertiary care cancer center for surgical resection of a skull-base malignancy was performed between 1980 and 2021. All children under 18 years of age with diagnosis of a skull-base sarcoma as confirmed with imaging and pathology were analyzed. RESULTS: A total of 21 children were identified but only four children with skull-base sarcomas had diagnostic imaging available in whom computer-assisted volumetric analyses were generated. In these cases, CAD/CAM was used to plan surgical approaches and intraoperative radiotherapy, significantly aiding in treatment for these complicated pediatric cases. CONCLUSION: CAD/CAM planning for oncologic resection has huge potential. Here we have shown its utility in pre-operative surgical planning and for administration of intraoperative radiation therapy. Future studies are needed to examine its value in facilitating intraoperative surgical management and patient outcomes, as well as cost effectiveness.

Understanding frozen section histopathology in Sinonasal and anterior skull base malignancy and proposed reporting guidelines.

BACKGROUND: Intraoperative frozen section histopathology (IFSH) in sinonasal and skull base surgery although widely used is not well studied. METHODS: We reviewed a database of sinonasal and anterior skull base tumors, between 1973 and 2019, and identified 312 suitable operative cases. Clinicopathologic data was collected and analyzed, in addition to descriptive data for histopathological reports classified as "ambiguous," or "limited/insufficient-quality/quantity." RESULTS: Overall, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for IFSH were 90.2%, 97.5%, 94.2%, 95.6%, and 95.2%, respectively. IFSH for adenocarcinoma, salivary carcinoma, and SCC all demonstrated a better clinical utility with a sensitivity of 90% or greater, while it was less than 90% for esthesioneuroblastoma, melanoma, and sarcoma. Other factors such as unclear reporting, poor quality specimens, or limited quality specimens were shown to lower diagnostic performance. Based on limitations identified, we proposed a novel IFSH reporting algorithm to improve IFSH in sinonasal and skull base surgery. CONCLUSIONS: IFSH is an accurate and clinically useful technique in sinonasal and skull base surgery patients; however, limitations exist.

Complications of Thyroid Cancer Surgery in Pediatric Patients at a Tertiary Cancer Center.

BACKGROUND: The incidence of complications and risk factors for hypocalcemia after pediatric thyroid cancer surgery has not been clearly defined in the literature because most reports fail to distinguish between benign and malignant disease. The trend away from total thyroidectomy (TT) to thyroid lobectomy in low-risk disease means there is a need to clearly define the complication profile of malignant disease. METHODS: After institutional review board (IRB) approval, a retrospective chart review was undertaken at Memorial Sloan Kettering Cancer Center for pediatric patients undergoing surgery for well-differentiated thyroid cancer from 1986 to 2021. Clinicopathologic characteristics and complications were evaluated. Multivariable analysis was performed to identify factors independently associated with postoperative hypocalcemia. RESULTS: The study identified 307 pediatric patients with well-differentiated thyroid carcinoma (median follow-up period, 61 months). Of these patients, 69% underwent TT and 31% received a partial thyroidectomy. Among them, 40% had N0 disease, 28% had N1a disease, and 33% had N1b disease. Postoperatively, no patients experienced a neck hematoma, 1.6% had temporary unilateral vocal cord palsy (VCP), and 0.7% had permanent VCP due to recurrent laryngeal nerve (RLN) invasion. Temporary and permanent hypocalcemia occurred in respectively 32.6 % and 5.2 % of the patients. Multivariable analysis identified central neck dissection (CND) (odds ratio [OR] 3.30; p < 0.001) and N1 disease (OR 2.51; p = 0.036) as independent risk factors for temporary hypocalcemia and N stage (OR 3.64; p = 0.018) as a risk factor for permanent hypocalcemia. CONCLUSION: Pediatric thyroid cancer surgery results in low complication rates despite nodal metastases. Vocal cord paralysis is rare unless disease is found to be invading the RLN intraoperatively. Both N stage and CND are independent risk factors for hypocalcemia, helping to identify high-risk patients.

Recurrent Differentiated Thyroid Cancer: The Current Treatment Options.

Differentiated thyroid carcinomas (DTC) have an excellent prognosis, but this is sometimes overshadowed by tumor recurrences following initial treatment (approximately 15% of cases during follow-up), due to unrecognized disease extent at initial diagnosis or a more aggressive tumor biology, which are the usual risk factors. The possible sites of recurrence are local, regional, or distant. Local and regional recurrences can usually be successfully managed with surgery and radioiodine therapy, as are some isolated distant recurrences, such as bone metastases. If these treatments are not possible, other therapeutic options such as external beam radiation therapy or systemic treatments should be considered. Major advances in systemic treatments have led to improved progression-free survival in patients previously considered for palliative treatments; among these treatments, the most promising results have been achieved with tyrosine kinase inhibitors (TKI). This review attempts to give a comprehensive overview of the current treatment options suited for recurrences and the new treatments that are available in cases where salvage surgery is not possible or in cases resistant to radioiodine.

Is Multifocality a Predictor of Poor Outcome in Childhood and Adolescent Papillary Thyroid Carcinoma?

CONTEXT: Total thyroidectomy in pediatric papillary thyroid carcinoma (PTC) is recommended in national guidelines because of the high incidence of multifocal disease (MFD). OBJECTIVE: To determine the incidence of MFD in childhood and adolescent vs adult PTC and whether MFD is a predictor for poorer outcomes in childhood and adolescent PTC. METHODS: We conducted an institutional review board-approved review of patients with PTC undergoing surgery (1986-2021) at Memorial Sloan Kettering Cancer Center. Clinical and pathological characteristics in patients with unifocal disease (UFD) and MFD were compared using Pearson's χ2 test. Survival outcomes were analyzed using the Kaplan-Meier method and log-rank test. Multivariate analysis assessed the impact of MFD on outcome. RESULTS: MFD was less common in childhood and adolescent patients with PTC (45%; 127/283) than in adults (54%; 3023/5564; P = .002). Childhood and adolescent patients with UFD and MFD had similar tumor stage and PTC subtype at presentation, with no significant difference in histopathologic features. Median follow-up was 68 months. There was no significant difference in 5-year recurrence-free probability and overall survival was 100% in both groups. There was no significant difference in 5-year contralateral lobe PTC-free probability between patients with UFD and MFD treated with lobectomy. Multivariate analysis showed MFD was not a predictor for recurrence. CONCLUSION: MFD was less common in childhood and adolescent patients with PTC than adults and was not a predictor of poor outcome on multivariate analysis, with excellent long-term outcomes in all patients with PTC. MFD does not appear to warrant completion thyroidectomy in childhood and adolescent patients selected for lobectomy.

Preoperative Evaluation of Thyroid Cancer: A Review of Current Best Practices.

OBJECTIVE: The incidence of thyroid cancer has significantly increased in recent decades. Although most thyroid cancers are small and carry an excellent prognosis, a subset of patients present with advanced thyroid cancer, which is associated with increased rates of morbidity and mortality. The management of thyroid cancer requires a thoughtful individualized approach to optimize oncologic outcomes and minimize morbidity associated with treatment. Because endocrinologists usually play a key role in the initial diagnosis and evaluation of thyroid cancers, a thorough understanding of the critical components of the preoperative evaluation facilitates the development of a timely and comprehensive management plan. The following review outlines considerations in the preoperative evaluation of patients with thyroid cancer. METHODS: A clinical review based on current literature was generated by a multidisciplinary author panel. RESULTS: A review of considerations in the preoperative evaluation of thyroid cancer is provided. The topic areas include initial clinical evaluation, imaging modalities, cytologic evaluation, and the evolving role of mutational testing. Special considerations in the management of advanced thyroid cancer are discussed. CONCLUSION: Thorough and thoughtful preoperative evaluation is critical for formulating an appropriate treatment strategy in the management of thyroid cancer.