Extranodal Extension Research Articles

Challenges and Considerations in Diagnosing and Managing p16+-Related Oropharyngeal Squamous Cell Carcinoma (OPSCC) with Neck Metastasis: Implications of p16 Positivity, Tobacco Exposure, and De-Escalation Strategies

Background: The incidence of patients showing neck metastasis and no obvious primary tumor at the initial diagnostic evaluation or neck cancer of unknown primary (NCUP) is rising. It is estimated that a relevant part of these tumors arises in the tonsillar crypts or base of the tongue and are p16+-related. However, today, the detection rate of the primary tumor is suboptimal. Identifying the primary tumor and its biomolecular characterization is essential since it influences the treatment administered, possibly reducing radiation fields and providing de-escalation to primary surgical management. However, p16 IHC (immunohistochemistry) might not be sufficient to diagnose HPV-related OPSCC. The other subset of patients discussed are the HPV-positive patients who have a history of tobacco exposure and/or p53 mutations. Possible factors that could negatively influence the outcomes of these patients are investigated and discussed below. So, this paper aims to analyze the diagnostic, bio-molecular, clinico-radiological, morphological, prognostic and therapeutical aspects of p16-positive OPSCC, highlighting the possible bias that can occur during the diagnostic and prognostic process. Methods: A narrative review was conducted to investigate the biases in the diagnostic and therapeutic process of two groups of patients: those who are p16-positive but HPV-negative patients, and those who are p16-positive and HPV-positive with exposure to traditional risk factors and/or p53 mutations. The keywords used for the literature research included the following: NCUP, OPSCC, p16IHC, HPV testing, p16 positive HPV negative OPSCC, p16 positive HPV positive OPSCC, tonsillectomy, tobacco exposure, p53 mutations, cystic neck metastasis, extranodal extension (ENE), radiotherapy, de-escalation and neck neck dissection. Results: HPV-positive OPSCC has specific clinico-radiological features. Bilateral tonsillectomy should be considered for the identification of the primary tumor. P16 IHC alone is not sufficient for diagnosing HPV-related OPSCC; additional detection methods are required. The role of tobacco exposure and p53 mutations should be investigated especially in cases of HPV-positive tumors. Extranodal extension (ENE) must be taken into consideration in the prognostic staging of HPV-positive tumors. Surgical primary treatment involving neck dissection (ND) and bilateral tonsillectomy followed by adjuvant radiation may represent the most appropriate approach for N3 cases. Diagnosis, prognosis and therapeutical implications must be addressed considering clinical, biomolecular and morphological aspects. At least today, the numerous biases that are still present influencing the diagnostic and prognostic process do not permit considering de-escalation protocols. Conclusions: A precise and accurate diagnosis is required in order to adequately stage and manage p16+ OPSCC, particularly with neck metastasis. The role of tobacco exposure and/or p53 mutations must be considered not only in p16+ OPSCC but especially in HPV-positive OPSCC. Until a more accurate diagnosis is possible, ENE should be considered even in p16+HPV+ OPSCC. Primary surgery with unilateral ND and bilateral tonsillectomy might be the treatment of choice given the numerous diagnostic and prognostic pitfalls. Therefore, it is inappropriate and risky to propose de-escalation protocols in routine clinical practice due to the risk of undertreatment.

Diving into hot topics of salivary gland carcinoma management—an EORTC young and early career investigator survey

IntroductionRecently, the ASCO and ESMO guidelines on salivary gland carcinomas (SGCs) have been released. However, several crucial points lack strong recommendations due to low or intermediate quality of evidence. To better address these “grey zones” in the guidelines, we conducted a survey among the European Organization for Research and Treatment of Cancer (EORTC) Head and Neck Cancer Group (HNCG) members on behalf of the EORTC young and early career investigators.Materials and methodsThe survey included 29 questions addressing diagnostic and therapeutic issues related to SGC patients and was shared among 539 members of the EORTC HNCG. Responses were collected from December 2022 to March 2023. The primary aim was to evaluate the decision-making criteria guiding physicians in areas with low evidence in SGC guidelines.ResultsWith a response rate of 19%, the survey received input from 102 respondents, mainly medical oncologists (45%). Among those with pathological high-risk features, 35% and 30% of respondents opted for chemoradiotherapy (CRT) in the definitive and adjuvant settings, respectively. For patients with R0 resection of highly aggressive SGC at the pT1–2 stage, 37% proposed a close follow-up, while 38% proposed adjuvant lymph-node field RT. In cases of pT3–4 stage, 48% proposed adjuvant lymph-node field RT in all cases, and 44% proposed it based only on risk factors. The most important factors guiding the decision to give adjuvant RT after salvage surgery for locoregional relapse include previous radiotherapy, margin status, and the presence of extranodal extension. When faced with combined positivity to HER2 and AR, responses regarding the choice of first-line palliative treatment were heterogeneous.ConclusionsInternational guidelines lack strong recommendations in several fields of SGC diagnosis and treatment due to insufficient high-quality data, resulting in heterogeneity in physicians’ treatment decision (e.g., adjuvant lymph-node field RT and their low concordance with guidelines, such as the use of concomitant CRT). The survey demonstrated the need for prospective clinical trial data to address these gaps in the future.

The Prognostic Importance of Radiologic Extranodal Extension in Hypopharyngeal Carcinoma.

Extranodal extension (ENE) had been included in the latest cancer staging system in hypopharyngeal squamous cell carcinoma (HypoSCC). However, the impact of ENE on HypoSCC survival and treatment outcomes are still unclear. Records from all HypoSCC patients diagnosed at the National Taiwan University Hospital from January 2007 to December 2018 were reviewed. All patients were divided into two groups, with or without ENE. Clinical features, pathological factors, and survival rates between the two groups were reviewed. We analyzed data from 388 HypoSCC patients, 125 (32.22%) with and 263 (67.78%) without ENE. The 5-year overall survival of the HypoSCC patients with radiological ENE, pathological ENE, and without ENE were 22.9%, 40.3%, and 55.5%. From the multivariate analysis, primary T3/T4 classification (p = 0.001) and radiological ENE (p < 0.001) were independent risk factors for disease-free and overall survival (OS). Finally, upfront neck dissection may significantly benefit disease-free survival (DFS) and neck nodal control in ENE+ (p = 0.002 and p = 0.007, respectively) or ENE- patients (p = 0.003 and p = 0.02, respectively). More than one-third of HypoSCC patients have ENE, with significantly lower OS and DFS. The upfront neck dissection could provide better DFS and neck nodal control.

Histopathological Prognostic Factors of Surgically Treated HPV-Associated Oropharyngeal Squamous Cell Carcinoma: A Systematic Review and Meta-analysis.

Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is rising in prevalence and is associated with better survival than HPV-negative OPSCC. In surgically treated HPV-negative OPSCCs, adverse pathologic features such as positive surgical margins, extra-nodal extension (ENE) and perineural invasion are well described to portend worse clinical outcomes. These adverse pathological features, however, are not validated prognostic markers among surgically treated HPV-positive OPSCCs. To that end, we pooled all available evidence to address the prognostic significance of these histologic features. This meta-analysis was performed according to PRISMA guidelines. PubMed, Web of Science and Embase databases were systematically searched for articles evaluating 13 known adverse histopathological prognostic factors of surgically treated HPV-associated OPSCC. Data analysis was done using R v4.0.5. A total of 32 studies (n = 31,535) fulfilled the inclusion criteria. ENE and advanced pT stage were associated with poorer overall survival (OS) [hazard ratio (HR):1.80, 95% confidence interval (CI) [1.59-2.03], p < 0.0001, HR: 3.28, 95% CI [2.20-4.87], p = 0.0025]; disease-specific survival (DSS) (HR: 3.14, 95% CI [1.20-8.26], p = 0.0327, HR: 3.49, 95% CI [2.45-4.96], p = 0.0043) and disease-free survival (DFS) (HR: 2.03, 95% CI [1.05-3.94], p = 0.0397, HR: 3.66, 95% CI [2.81-4.77], p = 0.0001) respectively. The presence of lymphovascular invasion (HR: 1.46, 95% CI [1.22-1.75], p = 0.0018) and positive margins (HR: 1.50, 95% CI [1.185-1.899], p = 0.0069) significantly worsen OS. ENE, advanced pT stage, positive margins and lymphovascular invasion were adverse histologic prognostic marker among surgically treated HPV-positive OPSCC. The presence of these factors should be carefully evaluated in order to select the optimal patients for surgical treatment.

Usefulness of Upfront Neck Dissection Before Chemoradiation Therapy for Head and Neck Squamous Cell Carcinoma.

Locally advanced squamous cell carcinoma of the head and neck (L/A SCCHN) is typically treated with surgery or chemoradiation therapy (CRT), whereas salvage surgery is considered for residual disease post-CRT. However, salvage surgery after radiation therapy presents challenges due to tissue fibrosis. Planned neck dissection (ND) combined with CRT, as well as positron emission tomography after CRT, have been proposed strategies, but no definitive consensus has been reached. Therefore, this study aimed to investigate the utility of "upfront ND" performed prior to CRT to enhance local control and reduce complications. We retrospectively reviewed 121 patients who underwent primary CRT for oropharyngeal, hypopharyngeal, or laryngeal cancer at Tokyo Medical University Hospital from January 2015 to September 2021. Patients without cervical lymph node metastasis or with unresectable nodes were excluded. All patients underwent pre-treatment imaging and staging. CRT consisted of intensity-modulated radiation therapy (IMRT) and cisplatin-based chemotherapy. Selective ND or modified radical neck dissection was performed based on lymph node involvement. Overall, 35 patients underwent upfront ND, whereas 54 did not. The upfront ND group exhibited significantly better 2-year locoregional recurrence-free survival than the group without upfront ND (93.7% vs. 71.0%). No significant differences were noted in adverse events between groups. The findings highlight upfront ND before CRT as a viable option for locally advanced head and neck cancer, particularly beneficial in cases with extranodal extension. This approach enhances local control and may reduce the need for salvage surgery, thus improving patient outcomes.

Prognostic significance of adjuvant therapy and specific radiation dosages in Taiwanese patients with oral cavity cancer and extra-nodal extension: a nationwide cohort study

BackgroundThe evidence for adjuvant chemoradiotherapy (CRT) of oral cavity squamous cell carcinoma (OCSCC) with extra-nodal extension (ENE) in National Comprehensive Cancer Network (NCCN) guidelines is derived from patients with head and neck cancer. The guidelines further suggest a radiation dose ranging from 6000 to 6600 cGy. In this nationwide study, we sought to evaluate the prognostic significance of adjuvant therapy and the specific radiation dosage in Taiwanese patients with pure OCSCC and ENE.MethodsA retrospective analysis of 1577 OCSCC patients with ENE who underwent resection and received adjuvant CRT or radiotherapy (RT) between January 2011 and December 2020 was conducted.ResultsMultivariable analysis revealed that adjuvant RT, more than four pathologically positive nodes, and radiation dosage below 6000 cGy were independent risk factors for unfavorable 5-year disease-specific survival (DSS) and overall survival (OS). Comparing patients who received CRT (n = 1453) to those treated with RT (n = 124) before and after propensity score (PS) matching, the 5-year outcomes were as follows: before PS matching, DSS (54% versus 30%, p < 0.0001), OS (42% versus 18%, p < 0.0001); after PS matching (n = 111 in each group), DSS (52% versus 30%, p = 0.0016), OS (38% versus 21%, p = 0.0019). For patients who underwent CRT, the 5-year outcomes for different radiation dose groups (6600 − 7000 cGy, n = 1155 versus 6000 − 6500 cGy, n = 199) were as follows: before PS matching, DSS (52% versus 54%, p = 0.1904), OS (43% versus 46%, p = 0.1610); after PS matching (n = 199 in each group), DSS (55% versus 54%, p = 0.8374), OS (46.5% versus 46.3%, p = 0.7578).ConclusionsFor OCSCC patients with ENE, our study shows CRT improved survivals than RT alone, underscoring the clinical significance of chemotherapy. Patients undergoing CRT with irradiation doses ranging from 6000 to 6500 cGy exhibited comparable survival outcomes to those receiving doses of 6600–7000 cGy. This observation suggests that irradiation doses exceeding the 6600 cGy may not confer the survival advantage in these patients. Further research is needed to confirm our results and explore the optimal irradiation dose for managing these patients.

The Prognostication of Surgically Resected Head and Neck Squamous Cell Carcinoma Using Pre-Therapy Neutrophil and Lymphocyte Counts.

Hematological markers, such as neutrophils (ANC), lymphocyte (ALC), and neutrophil-lymphocyte ratio (NLR), may serve as indicators of systemic inflammation and immune response in head and neck squamous cell carcinoma (HNSCC). However, their prognostic significance across HNSCC subtypes remains to be fully elucidated. We conducted a secondary analysis of a randomized clinical trial involving patients with surgically resected HNSCC with either positive margins or extranodal extension. These patients received either adjuvant chemoradiation with or without lapatinib. We explored the correlation between pre-therapy ANC, ALC, and NLR levels and overall survival (OS) as well as disease-free survival (DFS). A sub-group analysis examined potential links between these markers, primary tumor location, and HPV status. Of the 688 patients in the trial, we included 681 patients with documented pre-therapy ANC and ALC values. High pre-therapy ANC and ALC were significantly associated with reduced OS (HR, 1.56; 95% CI: 1.19-2.05) and (HR, 1.34; 95% CI: 1.01-1.79), respectively. High NLR did not significantly affect OS (HR, 1.09; 95% CI: 0.81-1.47). Subgroup analysis indicated significantly reduced OS in patients with high ANC across oropharyngeal, non-oropharyngeal, and HPV-negative subtypes. High ANC, ALC, and NLR did not impact DFS notably. Elevated pre-therapy ANC is strongly associated with decreased survival across all patients and subgroups, ALC was only significant in the general patient analysis. NLR's association with reduced OS was not statistically significant. These biomarkers may provide greater prognostic value in patients with oropharyngeal cancer and seemed to be more strongly associated with OS than DFS. Clinicaltrials.gov identifier: NCT00424255; URL: https://clinicaltrials.gov/ct2/show/study/NCT00424255.

Depth of invasion and extranodal extension: the influential factors to predict survival rate of patients with oral tongue squamous cell carcinoma

BackgroundCancer staging is essential in determining patients’ prognoses and designing the appropriate treatment strategy. American Joint Committee on Cancer has released the latest version of the staging system for tongue SCC. However, it is interesting to know whether this change in staging and the addition of depth of invasion (DOI) and the extra-nodal extension (ENE) have any influence on patients’ prognosis.MethodsIn this retrospective cohort study, the pathology records of patients with tongue SCC who underwent surgery at the Pathology Department of Cancer Institute Hospital, 2017–2021, were collected by referring to the hospital information system. Then the rate of change of pT, pN, and overall stage were assessed based on American Joint Committee on Cancer 7th and 8th editions.ResultsThe records of 204 patients were included in the final analysis. Significant changes in the staging system 2021 resulted in upstaging 64 patients (31.4%) in the overall stage, 91 patients (44.6%) in pT, and 30 patients (14.7%) in pN. The survival of upstaged patients was inferior compared to those without upstaging. However, this was not statistically significant for tumor and overall upstaging in the univariate analysis, while those with upstaged pN had significantly shorter survival. In the multivariate analysis, pT upstage also significantly impacted survival.ConclusionThis study showed the importance of pathology reports based on the latest edition of the American Joint Committee on Cancer, the accuracy in examining factors such as depth of invasion and extra-nodal extension.

Ninth Version of the AJCC and UICC Nasopharyngeal Cancer TNM Staging Classification

Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential. To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC. This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9). The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping. Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects. The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

Missed Adjuvant Therapy in Human Papillomavirus Positive Oropharyngeal Squamous Cell Carcinoma.

Investigate missed adjuvant therapy and associated disparities in overall survival (OS) for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). The 2010-2017 National Cancer Database was queried for patients with surgically resected HPV+ OPSCC. Indications for adjuvant radiotherapy (aRT) included pT3-4 classification, pN2-3 classification, lymphovascular invasion, pathologic extranodal extension (pENE), and/or positive surgical margins (PSM). Indication(s) for adjuvant chemoradiotherapy (aCRT) included pENE and/or PSM. Multivariable logistic and Cox regression models were implemented. Of 5297 patients satisfying inclusion criteria, 4288 had indication(s) for aRT; 775 did not receive any adjuvant therapy and were considered as missing aRT. A total of 2234 patients had indication(s) for aCRT. Of these, 1383 (61.9%) received aCRT, 555 (24.8%) patients received aRT alone and were considered as having missed aCRT, and 296 (13.2%) did not receive any adjuvant therapy. Missed aRT and missed aCRT were each associated with age, treatment facility type, pN classification, and surgical margin status (p < 0.015). Among patients with indication(s) for aRT alone, OS of those receiving no adjuvant therapy, aRT alone, and aCRT was 90.0%, 94.8%, and 93.4%, respectively (p = 0.080). Among patients with indication(s) for aCRT, those receiving aRT alone and aCRT had similar OS (89.0% vs. 86.6%, p = 0.357) which was superior to receiving no adjuvant therapy (74.9%, p < 0.001). These patterns in OS persisted on multivariable Cox regression. Among patients with HPV+ OPSCC and indication(s) for aRT, missed aRT was not associated with worse OS. For patients with indication(s) for aCRT, aRT alone was associated with similar OS as aCRT. 3 Laryngoscope, 2024.

7708 Navigating Thyroid Cancer With Differences in Thyroglobulin Assessment Techniques

Abstract Disclosure: M.S. Shah: None. S. Humayon: None. N.A. Mungo: None. This case report delves into the diagnostic journey of a patient with papillary thyroid carcinoma, emphasizing the importance of precise thyroglobulin measurement methods. The case highlights the differences between immunoassay and mass spectrometry in monitoring disease progression and treatment response.A 42-year-old female with a family history of thyroid-related issues, was found to have a thyroid nodule on physical exam. She underwent fine-needle aspiration (FNA) revealing papillary thyroid carcinoma, Bethesda category VI. Lymphatic invasion was present necessitating total thyroidectomy and lymph node dissection. Left level 3 and 4 lymph node excision showing 2 of 15 positive for metastatic papillary thyroid carcinoma without extranodal extension. Left superficial jugular lymph node excision showing 1 of 3 lymph node being positive for metastatic thyroid carcinoma without extranodal extension. RAI therapy and post-ablative scan showed focal moderate increased activity adjacent to the left hyoid bone. CT scan of the neck later showed stable appearance of the thyroidectomy bed with no new suspicious soft tissue mass. A small crescentic focus of enhancing soft tissue medial to the left common carotid artery is favored to represent residual thyroid tissue. Multiple small enhancing lymph node in the left neck at level llB and junction of levels ll and lll. Several of these are new or increased in size from prior examination and somewhat acidly enhanced. Although these are within normal limits by size criteria, recurrent diseases cannot be excluded. She underwent another surgical neck dissection with no cancer found. Given the negative findings, a shift from checking thyroglobulin (TG) from immunoassay to mass spectrometry was ideal.Patient was found to have persistent thyroglobulin elevation with Immunoassay, thyroglobulin level (60.5 ng/mL, n&amp;lt;35 ng/ml), without the presence of TG antibodies, whereas liquid chromatography-tandem mass spectrometry (LC-MS/MS) showing (&amp;lt;0.5 ng/mL), highlighting the methodological divergence. To date she has no imaging concerns and repeat testing from different labs similarly demonstrated undetectably Tg by LC-MS/MS and varying levels when tested by Immunoassay. Her levels by Immunoassay have trended down to her most recent level of (38 ng/ml).This case emphasizes the critical role of accurate thyroglobulin assessment in thyroid carcinoma follow-up. Immunoassay and mass spectrometry present divergent results, with LC-MS/MS proving more reliable in monitoring disease progression but more expensive and time consuming. Clinicians should consider the implications of methodological choices on patient management, particularly in cases of persistent elevation despite treatment. The potential discrepancies between these methods should be emphasized considering the impact on treatment decisions. Presentation: 6/1/2024

8791 A Case of Hyperfunctioning Thyroid Nodules Evaluated for Thyroid Metastasis in the Setting of Oropharyngeal Squamous Cell Carcinoma

Abstract Disclosure: M. Alashoor: None. J. Gogineni: None. A. Bakar: None. Introduction: Identifying and evaluating hyperfunctioning thyroid nodules in the setting of metastatic head and neck cancers represents a diagnostic challenge that may result in inaccurate identification of perithyroidal lymph node metastasis as malignant or metastatic thyroid nodules with standard workup. Case presentation: A 72-year-old male with a history of stage IV metastatic oropharyngeal squamous cell carcinoma, metastasized to the lymph nodes, lungs, mediastinum, and bilateral iliac bones. He was diagnosed two years ago and received chemotherapy, maintenance immunotherapy with pembrolizumab, and targeted palliative radiation therapy, with good clinical response. Restaging PET-CT two years later revealed local progression. During his workup, he was noted to have persistently abnormal thyroid function test with low TSH (0.03​​µIU/mL, n 0.3-5.33), normal free T4 (0.97ng/dL, n 0.60 - 1.40), mildly elevated free T3 (3.91pg/mL, n 2.5-3.9), negative thyrotropin receptor antibodies levels, negative TSI, negative TPO antibody, noted evidence of subclinical hyperthyroidism consistent over the past year. Radioactive iodine uptake demonstrated multinodular gland, mildly elevated 24-hour uptake of 28% consistent with hyperthyroidism, with decreased activity in the left lobe. Thyroid ultrasound revealed multiple probable malignant thyroid nodules, a 1.8 cm TI-RADS 5 lesion of the deep margin of the lower pole of the right lobe, and a 1.6 cm TI-RADS 5 lesion of the upper pole on the right lobe. He was treated with methimazole 5 mg. Further workup with fine needle aspiration demonstrated the right upper lobe nodule sample was positive for squamous cell carcinoma, findings suspicious for metastasis. He subsequently proceeded with radical tonsillectomy, right neck dissection, and right hemithyroidectomy. Surgical pathology results noted, right neck metastatic HPV-associated squamous cell carcinoma involving the lymph nodes with extranodal extension, right oropharyngeal HPV-mediated squamous cell carcinoma. The thyroid gland biopsy was significant for incidental papillary microcarcinoma 2mm, thyroid follicular nodular disease, without evidence of squamous cell carcinoma or metastatic infiltration. Post-hemithyroidectomy, his thyroid function normalized, and methimazole was discontinued. Conclusion: Thyroid metastasis from head and neck cancers represent a rare entity. In patients with a history of malignancy, evaluation of new thyroid masses remains crucial. While FNA is a sensitive method for detecting thyroid metastases, inaccuracies may occur, impacting the identification of thyroid nodules in the presence of local metastatic lymphadenopathy. Identifying squamous cell carcinoma in the thyroid can significantly influence the treatment plan of patients with metastatic carcinomas, therefore careful consideration must be undertaken on evaluation. Presentation: 6/1/2024

8675 Dosing of Radioactive Iodine for Papillary Thyroid Cancer in Advanced Chronic Kidney Disease

Abstract Disclosure: C. Cheatham: None. D. Beckman: None. INTRO Radioactive Iodine (RAI) ablation is an important treatment for patients diagnosed with papillary thyroid carcinoma. Most studies completed on RAI in renal dysfunction were focused on End Stage Renal Disease (ESRD) patients on dialysis to establish protocols on timing of dialysis to allow desired clinical response to RAI without increased risks and minimizing exposure of dialysis staff to radiation dose. The ideal RAI dosing and monitoring of patients with advanced chronic kidney disease (CKD) stage 4 or 5 not requiring dialysis has not been systematically reviewed. CASE 26 year-old female with CKD stage 4/5 secondary to chronic hydronephrosis from vesicoureteral reflux with baseline eGFR 15-20 mL/min/1.73 m2 was diagnosed with papillary thyroid cancer. She underwent total thyroidectomy with central and left lateral neck dissection, resulting in pathologic stage I, pT2 N1b M0 disease, high risk for recurrence according to the 2015 American Thyroid Association guidelines due to 17 positive lymph nodes from left level II-IV and VI, multiple with extranodal extension, as well as 1 vessel angioinvasion. She was referred for adjuvant RAI ablation after withdrawal from thyroid hormone. Decision was made to proceed with a 50% dose reduction and close monitoring of radioactivity clearance as an inpatient given decrease of eGFR to 10-12 mL/min/1.73 m2. She was cleared for discharge 4 days after RAI dose of 74.8mCi when activity level dropped to &amp;lt;2mR/hr. Post-ablation whole body scan showed activity in the thyroid bed and parasternal notch without evidence of metastatic disease. Post-treatment non-stimulated thyroglobulin 6 weeks later was 0.4 ng/mL down from 269.7 ng/mL. DISCUSSION Given RAI is predominately renally cleared, decreased renal function affects clearance rates and associated exposure to radiation. Risks with decreased RAI clearance include bone marrow toxicity and prolonged isolation requirements. In a 2017 retrospective review, patients with eGFR &amp;lt;30 mL/min/1.73 m2 had delayed clearance leading to a mean proportional reduction of exposure rate at 48 hours of -67.2% compared to -94.3% in healthy controls. While protocols exist for patients on hemodialysis, no such protocols have been established for patients with advanced CKD not requiring dialysis. For this patient, after multidisciplinary discussion with nuclear medicine, health physics, and nephrology in setting of further eGFR reduction during hormone withdrawal, decision was made to reduce the intended dose by 50% with inpatient monitoring and backup to dialyze if no significant decrease in radiation activity level was seen or if she were to progress to anuric or oliguric renal failure. This case highlights the need for established protocols and long-term studies to evaluate risk and treatment response in relation to dosing of RAI in this population, but a 50% dose reduction appears to be effective without adverse event. Presentation: 6/2/2024

7357 Microscopic Papillary Thyroid Cancer Presenting with Cranial Nerve Palsies due to Metastatic Cervical Lymphadenopathy: A Case Report

Abstract Disclosure: N.N. Mukhtar: None. C. Zuo: None. B.R. Haugen: None. Introduction: Tumors metastasizing to head and neck are considered a rare cause of cranial nerve palsy (CNP). In this report, we describe an unusual presentation of metastatic microscopic follicular variant papillary thyroid cancer (FVPTC) presenting with CNP. Case Summary: A 68-year-old previously healthy female presented to her primary care physician with a 6-week history of difficulty speaking and chewing food. She did not notice any dysphagia, change in voice or shortness of breath. Cranial nerve examination was evident for palatal asymmetry, left-sided uvular and right-sided tongue deviations suggesting right glossopharyngeal and hypoglossal nerve palsies. Neck examination revealed a normal thyroid gland without palpable nodules however, the patient had multiple enlarged painless right cervical lymph nodes (CLN). MRI of the brain was normal. CT of the neck and chest showed enlarged, calcified right level II and III CLN (largest 4x3.5 cm) compressing the right internal jugular vein. In addition, bilateral pulmonary nodules (largest 1.7x1.5 cm) suspicious for metastasis were seen. CT-guided biopsy of left upper lobe lung nodule was consistent with metastatic thyroid cancer (positive PAX-8 and TTF-1 immunostaining). Neck ultrasound did not show any thyroid nodules, but did confirm 4 enlarged right CLN (largest 2.9 cm). The patient was referred to our multidisciplinary clinic for further evaluation. Based on the duration of her symptoms (6 weeks), her CNP was most-likely irreversible and agreement to proceed with total thyroidectomy, central and right lateral neck dissection aiming for complete resection in preparation for future treatment with radioactive iodine. Preoperative thyroglobulin level was 30.7 ng/ml (1.6-50), thyroglobulin antibody 24 U/mL (&amp;lt;40) and TSH 0.6 mIU/L (0.4-4.6). Intra-operatively; the patient had extensive, bulky lymphadenopathy extending to surrounding neck muscles and completely encasing right jugular vein. Histopathological examination of the resected tissue showed a unifocal right thyroid lobe microscopic (6x4x3 mm) infiltrative follicular variant papillary thyroid cancer (FVPTC). No extrathyroidal extension, necrosis, angioinvasion or lymphatic invasion were identified. Mitotic index was 3/ 2mm2. 13 out of 36 lymph nodes were positive for metastatic thyroid cancer (3/3 level II, 2/17 level III, 8/16 level IV), largest was 4.6 cm with extra-nodal extension. The patient was discharged on suppressive dose levothyroxine. Molecular studies: Next generation sequencing of the lung biopsy was negative for BRAFV[6]00E mutation and further molecular analyses are ongoing. Conclusion: This case describes two unique presentations of thyroid cancer; a microscopic FVPTC associated with large lateral cervical lymph node metastasis and, CNP as the initial presentation of thyroid cancer which to our knowledge, has not been reported previously. Presentation: 6/2/2024

Correlation of Lymph Node Characteristics and Extranodal Extension in Oral Cavity Squamous Cell Carcinoma.

Identify correlations between lymph node characteristics and extranodal extension (ENE). Retrospective chart review. Tertiary care center. Patients who underwent neck dissection for oral cavity squamous cell carcinoma from 2004 to 2018 were included, with a starting sample of 496. The primary outcome was ENE in at least 1 lymph node. Additional variables included number of dissected nodes, positive nodes by level, positive lymph node ratio (LNR), and diameter of metastatic deposit and ENE focus. Univariate and multivariate binary logistic regression analyses were performed to determine correlations between included variables and ENE. Of the 496 patients, 233 had nodal metastasis (47.0%). 13,814 nodes were removed, with 714 (5.2%) containing metastasis. Of the positive nodes, 28.0% had ENE, 47.2% did not have ENE, and 24.8% were unknown. The mean ENE diameter was 5.1 mm (SD, 9.9). On univariate logistic regression analysis, ipsilateral neck LNR per 0.1 unit increase (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.02-1.32, P = .02), metastatic deposit size per 1 mm increase (OR 1.06, CI 1.04-1.08, P < .0001), and clinical T- (P = .02) and N-class (P = .0003) significantly correlated with ENE. On multivariate logistic regression analysis, size of metastatic deposit (OR 1.06, CI 1.03-1.08, P < .0001) remained significantly correlated with ENE. Controlling for confounding variables, size of metastatic deposit was an independent predictor of ENE, suggesting that as the metastatic deposit size increases, the odds of extension through the capsule also increases. This may be due to capsule thinning as the deposit grows or could represent the invasive nature of aggressive disease.

Association of Hashimoto thyroiditis with papillary thyroid carcinoma and its clinical features – A retrospective study in a tertiary care hospital

Background: Papillary thyroid carcinoma (PTC) is the most widespread endocrine malignancy. Among the several risk factors, Hashimoto thyroiditis (HT) is one of the factors associated with increased incidence of PTC. Both HT and PTC share several epidemiologic features including high prevalence, female predominance, and increased incidence in iodine-sufficient areas. Aims and Objectives: The aim of the study was to assess the incidence of HT and PTC coexistent in endemic population. The study also aimed to determine the association of various prognostic parameters of PTC in patients with coexistent HT. Materials and Methods: This was a retrospective study done from May 2019 to May 2024 over a period of 5 years in a tertiary care hospital of West Bengal. A total of 54 patients with primary PTC who underwent total thyroidectomy with cervical lymph node dissection (LND) were studied. Patients with primary PTC with neck LND and complete medical history were included in this study. Patients with previous thyroidectomy surgery or patients with incidental PTC diagnosed in thyroidectomy specimens done for a benign neoplasm (without LND) were excluded from the study. Results: A total of 54 cases of PTC were studied out of which 23 cases were PTC associated with HT and 31 cases were PTC without HT constituting 42.59% and 57.4%, respectively. PTC associated with HT had a greater incidence in females. In this study, our results showed that PTC with HT had a greater tendency of tumor multifocality, greater mean lymph node size, and increase rate of extranodal tumor extension. At the same time, patients of PTC associated with HT had smaller tumor size and low clinical stage. Conclusion: PTC associated with HT had a female preponderance, larger metastatic lymph node, a tendency for multifocality, and extranodal extension. At the same, they also had smaller tumor size and low clinical stage indicating a complex and controversial effect of HT on PTC.

Determinants of Prognosis in Head and Neck Cutaneous Squamous Cell Carcinoma With Nodal Metastases

The eighth edition tumor, node, metastasis (TNM) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) is a poor predictor of survival in patients with lymph node metastases, possibly due to the inclusion of extranodal extension (ENE). To identify the key determinants of prognosis in patients with nodal metastatic HNcSCC and analyze the association of ENE with TNM stage and investigate for prognostic heterogeneity in ENE-positive disease. This retrospective, multicenter cohort study was conducted at 4 Australian tertiary referral centers using prospectively collected data in patients treated between 1980 and 2017 with a median (IQR) follow-up of 3.2 (3.9) years. The study population included 1309 consecutive patients with HNcSCC that was metastatic to parotid and/or cervical nodes. After excluding cases with perioperative mortality, missing data, or follow-up, the final study population included 1151 patients. Curative intent surgery ± adjuvant radiotherapy. Differences in locoregional control (LRC), disease-specific survival (DSS), and overall survival were determined using Cox regression analysis. Among 1151 patients, 976 (84.8%) were male and 175 (15.2%) female, with a median age of 73.3 years (range, 18-100 years). On multivariable analysis, immunosuppression (hazard ratio [HR], 2.48; 95% CI, 1.64-3.74), perineural invasion (HR, 1.69; 95% CI, 1.25-2.30), ENE (HR, 1.53; 95% CI, 0.95-2.44), size (>3-6 cm vs ≤3 cm [HR, 1.41; 95% CI, 1.03-1.93]; >6 cm vs ≤3 cm [HR, 5.01; 95% CI, 2.98-8.42]), and number of nodal metastases (3-4 vs 1-2 [HR, 1.54; 95% CI, 1.01-2.34]; ≥5 vs 1-2 [HR, 2.86; 95% CI, 1.99-4.11]) were associated with DSS. Similar results were found for LRC and overall survival. More than 90% of the population was categorized as TNM stage IV, with 32% attributable to ENE. In the ENE-positive subset (n = 860), DSS ranged from 8% to 88% based on stratification using other clinicopathological factors. The study results suggest that immunosuppression, perineural invasion, ENE, and size and number of nodal metastases are associated with reduced survival and LRC in HNcSCC with nodal metastases. The inclusion of ENE in HNcSCC staging needs to be reassessed, as it ascribes excessive importance to ENE and upstages most patients to TNM stage IV, despite many having a high chance of cure.

Central Neck Dissection in Papillary Thyroid Carcinoma: Benefits and Doubts in the Era of Thyroid Lobectomy.

Surgery is still the main line of treatment for papillary thyroid cancer (PTC) with a current trend for de-intensified treatment based on an excellent prognosis. The role of a routine prophylactic central neck dissection (PCND) is still debated as its impact on oncologic outcomes has never been cleared by a randomized clinical trial. In this study, we aimed to report our long-standing experience in PCND and its potential contemporary role in the treatment of PTC. A retrospective institutional review was performed on all patients who underwent operation for PTC including PCND between 1998 and 2021. The primary outcomes were the rate of central lymph node metastases (CLNMs), cancer recurrence and incidence of complications. Survivals were analyzed using the Kaplan-Meier estimator and Cox proportional hazard models. A total of 657 patients were included in this study with a median follow-up of 78 months (48-114 months). Two hundred and one patients presented occult CLNMs (30.6%). The presence of a pathological node represented the unique reason for a completion thyroidectomy and I131 therapy in 12.5% of the population. Age lower than 55 years, microscopic or macroscopic extra-thyroid extension (ETE) and multifocality were independent factors predicting CLNMs. The rate of recurrence in the whole population was 2.7% (18 patients). Five-year and ten-year disease-free survival (DFS) was 96.5% (94.7-97.7) and 93.3% (90.3-95.5), respectively. Two patients relapsed in the central neck compartment (0.3%). Age (>55 years), pathological staging (pT) and extranodal extension (ENE) were independent factors associated with a worse DFS. The rate of temporary and permanent vocal fold palsy was 12.8% and 1.8%, respectively, and did not depend on the type of surgical procedure performed. Hypoparathyroidism was temporary in 42.2% and permanent in 11.9% of the patients. A sub-analysis upon cT1b-T2 patients treated primarily with thyroid lobectomy and ipsilateral PCND demonstrated a 2.6% rate of permanent hypoparathyroidism. PCND allows for a high disease-free survival and a proper selection of patients needing adjuvant treatment, in particular, those treated with a unilateral procedure. On the other hand, bilateral approach is burdened by a not-neglectable rate of permanent hypoparathyroidism.

Prevention of radiation induced dermatitis in head and neck cancer patients using cryptomphalus aspersa secretion.

Radiotherapy (RT) is a technique widely used in oncology, acquiring special prominence in head and neck cancer (HNC). RT of HNC may be associated with secondary effects including skin reaction, being dermatitis the most common radio-induced side effect during treatment. The use of a wide variety of agents is reported to handle skin toxicity. The aim of the present work is to evaluate the different level-concentration of Snail Cryptomphalus Aspersa (SCA) that best protect from radiation-induced radiodermatitis in HNC. We performed a single institutional pilot study to assess the skin toxicity with 0%, 5%, 10% and 15% SCA concentration during RT treatment and 1 and 3months after the treatment finished according to the Radiation Therapy Oncology Group (RTOG) scoring. A total of 72 patients with HNC diagnosis who received RT with/without Chemotherapy (Ch) between January of 2018 and June of 2020 were assessed. Radiodermatitis grade was stastistically correlated with the SCA level-concentration and with the influence of extranodal extension status (ENE). A reduction in the rate of grade ≥ II patients' dermatitis was dependent on SCA level-concentration. We found that with higher SCA level-concentration (10 and 15%, patients had 34 and 38% grade ≥ II respectively), this was less than with 0 and 5% SCA level-concentration where a 58% radiodermatitis grade ≥ II was found by Cox regression analysis; p = 0.017 and p = 0.045 respectively. We could conclude that the application of a 10-15% SCA level-concentration after adjusting by ENE, was the best concentration to reduce the rate of grade ≥ II radiodermatitis.

The prognostic implications of radiologic extranodal extension in the lymph nodes of patients with nasopharyngeal cancer.

Objective: This study was developed to explore the prognostic relevance of radiologic extranodal extension (rENE) in lymph node-positive nasopharyngeal carcinoma (NPC) patients. Materials and methods: A retrospective review of data from 249 eligible patients with NPC was performed, with magnetic resonance imaging scans being used for rENE grading. The prognostic value of rENE was assessed through univariate and multivariate analyses. Results: Log-rank tests revealed significant differences between patients with and without rENE in terms of overall survival, progression-free survival (PFS) and distant metastasis-free survival (DMFS). G2 and G3 patients tended to exhibit worse PFS and DMFS relative to G0/G1 patients (p <0.05). Long-term chemotherapy cycles were associated with significant improvements in the PFS and DMFS of G2 and G3 patients. Conclusion: These results suggest that higher rENE grades (G2/G3) are independently associated with worse survival outcomes among NPC patients, with more aggressive treatment strategies potentially affording greater prognostic benefits to these individuals.