Impact of comorbidities on immediate post-operative complications in oral cavity free flap patients.

PURPOSE: To examine the relationship between comorbidities and the development of immediate post-operative complications in patients undergoing oral cavity composite resection (OCCR) with free flap (FF) reconstruction. MATERIALS AND METHODS: Retrospective analysis was completed on all consecutive OCCRs with FF reconstruction performed at a single quaternary care facility between 1999 and 2020. Comorbidities, immediate post-operative complications, patient demographics, and tumor characteristics were collected. Odds ratios (OR) with 95 % confidence intervals were calculated for associations between comorbidities and immediate post-operative complications. RESULTS: 320 patients who underwent OCCR with FF reconstruction were included. One hundred twenty-one (37.8 %) patients developed a post-operative complication during their initial hospital admission. The most common complications were non-pneumonia cardiopulmonary events (14.1 %), pneumonia (9.4 %), and wound infection (8.4 %). Other complications included flap compromise, bleeding, and fistula. On multivariate analysis, patients without comorbid conditions were less likely to develop a post-operative complication (OR 0.64; 0.41-0.98). Atrial fibrillation (OR 2.94; 1.17-7.39) and cerebrovascular disease (OR 2.28; 1.08-4.84) were associated with increased odds of developing any complications. Furthermore, cerebrovascular disease (OR: 2.33; 1.04-5.39) and peripheral vascular disease (OR: 2.7; 1.2-6.08) were independently associated with pneumonia. CONCLUSION: In this retrospective review of patients undergoing OCCR with FF reconstruction for oral cavity SCC, lack of identifiable comorbidities appeared to be protective for post-operative complications while atrial fibrillation and cerebrovascular disease were associated with increased odds of any complication. Pre-existing vascular disease was also associated with an increased risk of pneumonia.

Impact of COVID-19 on presentation, staging, and treatment of head and neck mucosal squamous cell carcinoma.

OBJECTIVES: During the COVID-19 pandemic, maintenance of safe and timely oncologic care has been challenging. The goal of this study is to compare presenting symptoms, staging, and treatment of head and neck mucosal squamous cell carcinoma during the pandemic with an analogous timeframe one year prior. MATERIALS AND METHODS: Retrospective cohort study at a single tertiary academic center of new adult patients evaluated in a head and neck surgical oncology clinic from March -July 2019 (pre-pandemic control) and March - July 2020 (COVID-19 pandemic). RESULTS: During the pandemic, the proportion of patients with newly diagnosed malignancies increased by 5%, while the overall number of new patients decreased (n = 575) compared to the control year (n = 776). For patients with mucosal squamous cell carcinoma (SCC), median time from referral to initial clinic visit decreased from 11 days (2019) to 8 days (2020) (p = 0.0031). There was no significant difference in total number (p = 0.914) or duration (p = 0.872) of symptoms. During the pandemic, patients were more likely to present with regional nodal metastases (adjusted odds ratio (OR) 2.846, 95% CI 1.072-3.219, p = 0.028) and more advanced clinical nodal (N) staging (p = 0.011). No significant difference was seen for clinical tumor (T) (p = 0.502) or metastasis (M) staging (p = 0.278). No significant difference in pathologic T (p = 0.665), or N staging (p = 0.907) was found between the two periods. CONCLUSION: Head and neck mucosal SCC patients presented with more advanced clinical nodal disease during the early months of the COVID-19 pandemic despite no change in presenting symptoms.

Neuroendocrine carcinomas of the head and neck: A small case series.

INTRODUCTION: Neuroendocrine tumors of the head and neck are rare and arise either from epithelial or neuronal origin. Debate continues over the classification systems and appropriate management of these pathologies. OBJECTIVE: By investigating a small set of cases of high grade epithelial-derived neuroendocrine tumors of the head and neck (neuroendocrine carcinomas or NEC) from one institution, we compare survival rates of NEC of the head and neck to pulmonary NEC. METHODS: We identified patients from pathology records with neuroendocrine carcinomas of the head and neck and retrospectively collected clinical data as well as immunohistochemical (IHC) staining data. RESULTS: We identified 14 patients with NEC, arising from the parotid (n = 5), nasal cavity (n = 4), larynx (n = 2), and other regions (n = 2). One additional patient had NEC arising in two sites simultaneously (parotid and nasal). Staining patterns using IHC were relatively consistent across specimens, showing reactivity to chromogranin and synaptophysin in 73% and 100% of specimens, respectively. Treatment courses varied across patients and included combinations of surgery, chemotherapy, and/or radiation. The overall survival rate at 1, 2, and 5 years of these patients was 56%, 56%, and 43% with a mean follow-up time of 2.12 years. CONCLUSION: Compared to NEC arising in the lung, this subset of patients had better survival rates, but worse survival rates than the more common squamous cell carcinoma of the head and neck.

Transcervical sonography and human papillomavirus 16 E6 antibodies are sensitive for the detection of oropharyngeal cancer.

BACKGROUND: Human papillomavirus 16 (HPV-16) E6 seropositivity is a promising early marker of human papillomavirus-driven oropharyngeal cancer (HPV-OPC), yet more sensitive imaging modalities are needed before screening is considered. The objective of this study was to determine the sensitivity of transcervical sonography (TCS) for detecting clinically apparent HPV-OPC in comparison with computed tomography (CT) and positron emission tomography (PET)/CT. METHODS: Fifty-one patients with known or suspected HPV-OPC without prior treatment underwent oropharyngeal TCS and blood collection (for HPV multiplex serology testing). Eight standard sonographic images were collected; primary-site tumors were measured in 3 dimensions if identified. Each patient underwent a full diagnostic workup as part of standard clinical care. The pathologic details, HPV status, final staging, and imaging findings were abstracted from the medical record. The sensitivity of each imaging modality was compared with the final clinical diagnosis (the gold standard). RESULTS: Twenty-four base of tongue cancers (47%), 22 tonsillar cancers (43%), and 2 unknown primary cancers (4%) were diagnosed; 3 patients (6%) had no tumors. All p16-tested patients were positive (n = 47). Primary-site tumors were correctly identified in 90.2% (95% confidence interval [CI], 78.6%-96.7%) with TCS, in 69.4% (95% CI, 54.6%-81.7%) with CT, and in 83.3% (95% CI, 68.6%-93.0%) with PET/CT. TCS identified tumors in 10 of 14 cases missed by CT and recognized the absence of tumors in 3 cases for which CT or PET/CT was falsely positive. The smallest sonographically identified primary-site tumor was 0.5 cm in its greatest dimension; the average size was 2.3 cm. Among p16-positive patients, 76.1% (95% CI, 61.2%-87.4%) were seropositive for HPV-16 E6. CONCLUSIONS: TCS and HPV-16 E6 antibodies are sensitive for the diagnosis of HPV-OPC.

Free dermal fat graft reconstruction of the head and neck: An alternate reconstructive option.

OBJECTIVES: Ablative procedures of the head and neck often result in significant facial and cervical irregularities and cosmetic asymmetry. The deformity resulting from ablative procedures of the head and neck is a significant source of cosmetic morbidity and postoperative dissatisfaction. Reconstruction of post-ablative defects in the head and neck can employ a broad range of techniques, ranging from primary closure to free tissue transfer. The free dermal fat graft (FDFG) is one such option and has been used to repair volume defects of varying sizes after common head and neck procedures such as parotidectomy. However, its use is largely undocumented in the literature. We seek to further illustrate the FDFG as an alternate method of reconstruction of head and neck defects. STUDY DESIGN: Non-randomized retrospective analysis. METHODS: The medical records of all patients who underwent primary autologous abdominal FDFG reconstruction of head and neck defects by a single surgeon at Vanderbilt University Medical Center from January 1997 to August 2010 were reviewed. All patients were called in order to assess their post-operative cosmetic satisfaction. RESULTS: Sixty-two patients were analyzed. Only three patients were found to have post-operative complications directly related to the FDFG. No complications were found at the donor site. Based on a telephone survey, the majority of patients were satisfied post-operatively with their cosmetic outcomes in the primary site and donor site. CONCLUSIONS: From our experience the FDFG is a cosmetically and functionally advantageous option for reconstruction of ablative procedures of the head and neck.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: THE INCREASING INCIDENCE OF THYROID CANCER.

OBJECTIVE: (1) Describe current epidemiology of thyroid cancer in the United States; (2) evaluate hypothesized causes of the increased incidence of thyroid cancer; and (3) suggest next steps in research and clinical action. METHODS: Analysis of data from Surveillance, Epidemiology and End Results System and the National Center for Vital Statistics. Literature review of published English-language articles through December 31, 2013. RESULTS: The incidence of thyroid cancer has tripled over the past 30 years, whereas mortality is stable. The increase is mainly comprised of smaller tumors. These facts together suggest the major reason for the increased incidence is detection of subclinical, nonlethal disease. This has likely occurred through: health care system access, incidental detection on imaging, more frequent biopsy, greater volumes of and extent of surgery, and changes in pathology practices. Because larger-size tumors have increased in incidence also, it is possible that there is a concomitant true rise in thyroid cancer incidence. The only clearly identifiable contributor is radiation exposure, which has likely resulted in a few additional cases annually. The contribution of the following causes to the increasing incidence is unclear: iodine excess or insufficiency, diabetes and obesity, and molecular disruptions. The following mechanisms do not currently have strong evidence to support a link with the development of thyroid cancer: estrogen, dietary nitrate, and autoimmune thyroid disease. CONCLUSION: Research should focus on illuminating which thyroid cancers need treatment. Patients should be advised of the benefits as well as harms that can occur with treatment of incidentally identified, small, asymptomatic thyroid cancers.

How Often is Cancer Present in Oral Cavity Re-resections After Initial Positive Margins?

OBJECTIVE: To evaluate the rate at which carcinoma is present in the re-resection specimen following initial positive margins during head and neck cancer surgery and its impact on oncologic outcomes. STUDY DESIGN: Retrospective chart review. METHODS: A single institution retrospective chart review of patients that underwent curative-intent surgery for oral cavity cancer was performed. Final pathology reports were reviewed to identify patients with initial positive margins who underwent re-resection during the same operation. Initial positive margin was defined as severe dysplasia, carcinoma in situ (CIS), or carcinoma. Cox proportional hazards and Kaplan-Meier analyses were used to assess for associations with survival outcomes. RESULTS: Among 1873 total patients, 190 patients (10.1%) had initial positive margins and underwent re-resection during the same surgery. Additional carcinoma, CIS, or severe dysplasia was found in 29% of re-resections, and 31% of patients with initial positive margins had final positive margins. Half of the patients with a final positive margin had a positive margin at an anatomic site different than the initial positive margin that was re-resected. The median follow-up was 636 days (range 230-1537). Re-resection with cancer and final positive margin status was associated with worse overall survival (OS; p = 0.044 and p = 0.05, respectively). However, only age, T4 disease, and surgery for recurrent oral cavity cancer were independently associated with OS (p < 0.001, p = 0.005, and p = 0.001, respectively). CONCLUSIONS: Fewer than a third of oral cavity re-resections contain further malignancy, which may suggest that surgeons have difficulty relocating the site of initial positive margin. Final positive margins are often at anatomic sites different than the initial positive margin. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:717-724, 2024.

Virtual 3D Specimen Mapping in Head & Neck Oncologic Surgery.

OBJECTIVES: Virtual 3D specimen mapping of oncologic surgical specimens provides a visual record of the specimen and margin sampling sites which can be utilized in a variety of cancer care settings. Our objective was to perform a retrospective review of head and neck surgical oncology cases where the specimen was mapped post-operatively and to evaluate the utility of these 3D specimen maps amongst the multidisciplinary cancer care team. METHODS: A retrospective review of our 3D specimen model biorepository was performed. Surgical specimens were 3D scanned and then graphically annotated (or "mapped") during routine pathologic processing. The resulting 3D specimen maps were distributed to the multidisciplinary oncologic care team. Final margin status and any use of the 3D specimen maps were recorded. RESULTS: A total of 28 cases were included. Virtual 3D specimen maps were utilized by the cancer care team in 8 cases (29%), including 2 positive margin cases, 2 close margin cases, and 4 indeterminate margin cases. 3D specimen maps were used to visualize positive margin sites for pathologist-surgeon communication as a visual reference during tumor board discussions and to inform radiation treatment planning. CONCLUSION: Post-operative virtual 3D specimen mapping of oncologic specimens creates a permanent visual record of the specimen and the margins sampled and may serve as a beneficial tool for communication amongst the multidisciplinary cancer care team. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:191-197, 2024.

Wnt/ß-catenin signaling is a therapeutic target in anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly aggressive malignancy that has consistently shown Wnt/ß-catenin (canonical) signaling activation in various study populations. There are currently no targetable treatments for BRAF-wildtype ATC and a lack of effective treatment for BRAFV600EATC. Our aim is to identify whether Wnt inhibitors could be potential therapeutic agents for ATC patients with limited treatment options. METHODS: In this Institutional Review Board-approved study, we utilize a cohort of 32 ATCs and 20 non-neoplastic multinodular goiters (MNG). We also use 4 ATC spheroid cell lines (THJ-16T, THJ-21T, THJ-29T, and THJ-11T) and two primary patient-derived ATC organoid cultures (VWL-T5 and VWL-T60). Finally, we use a murine xenograft mouse model of ATC for in vivo treatment studies. RESULTS: Using a large patient cohort, we demonstrate that this near-universal Wnt signaling activation is associated with ligand expression- rather than being mutationally-driven. We show that pyrvinium pamoate, a potent Wnt inhibitor, exhibits in vitro efficacy against both ATC cell lines and primary patient-derived ATC organoids VWL-T5 (p < 0.05) and VWL-T60 (p < 0.01) Finally, using a murine xenograft model of ATC, we show that pyrvinium significantly delays the growth of ATC tumors in THJ-16T (p < 0.005) and THJ-21T (p < 0.001). CONCLUSIONS: We tested Wnt inhibitor treatment, both in vitro and in vivo, as a potential novel therapy for this highly lethal disease. Future large-scale studies utilizing multiple Wnt inhibitors will lay the foundation for the development of these novel therapies for patients with ATC.

A model for improving the health and quality of life of single mothers in the developing world.

Among the impoverished population of coastal Kenya, there is a rapidly growing group of young single mothers who suffer from adverse health outcomes, incomplete schooling, social ostracism by their communities, and economic hardship. To address this problem, in 2008 the Single Mothers Program (SMP) selected a group of vulnerable single mothers, provided them with basic relief and education, equipped them with training and start-up capital to run their own businesses, and assessed the impact of the program via a pre- and post-implementation survey. After two years in the program, a majority of the single mothers increased their contraceptive use, increased their degree of literacy, increased their individual incomes, and were more positively perceived by their communities. This study demonstrates a program model that can be used to improve the health and quality of life of single mothers and their children in similar communities throughout the world.

The computer-aided design margin: Ex vivo 3D specimen mapping to improve communication between surgeons and pathologists.

BACKGROUND: Numerous challenges exist in determining surgical margin status. Communication between surgeons and pathologists is crucial for specimen orientation and accurate margin assessment. METHODS: A prospective study to determine feasibility of incorporating three-dimensional (3D) scanning into surgical pathology workflow was performed. A structured-light 3D scanner captured the photorealistic surface topography of fresh surgical specimens. Computer-aided design (CAD) software was used to document sites of margin sampling and sectioning. Surveys were distributed among faculty and staff stakeholders to assess feasibility. RESULTS: A series of 40 cases were 3D-scanned. Median image acquisition time was 8 min. The majority of respondents agreed that the experimental 3D system helped achieve clearer communication. 3D specimen maps assisted in the communication of a focally positive or close margin in 4 of 17 cases. CONCLUSIONS: Routine 3D scanning and specimen mapping is feasible and represents an innovative approach to intraoperative and final pathology documentation, margin analysis, and surgeon-pathologist communication.

Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction.

Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.

Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5-Year Update.

The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.

Intensity-modulated radiation therapy with concurrent carboplatin and paclitaxel for locally advanced head and neck cancer: toxicities and efficacy.

BACKGROUND: Intensity-modulated radiation therapy (IMRT) and alternative chemotherapy regimens strive to maintain efficacy while minimizing toxicity in locally advanced head and neck cancer (LAHNC) treatment. Our experience with concurrent IMRT and taxane-based chemotherapy is presented. METHODS: A retrospective review of 150 consecutive patients with LAHNC treated with IMRT and concurrent taxane-based chemotherapy with curative intent was performed. The IMRT fractionation regimen consisted of 69.3 Gy to gross disease (2.1 Gy/fraction) and 56.1 Gy to prophylactic nodal sites (1.7 Gy/fraction). Weekly paclitaxel (30 mg/m(2)) and carboplatin (area under the concentration-time curve [AUC], 1) were given concurrently to all patients, and 69% received weekly induction with paclitaxel (60 mg/m(2)) and carboplatin (AUC, 2). RESULTS: Over 90% of patients received the prescribed radiation dose. Ninety-six percent completed five or more cycles of concurrent chemotherapy, with similar tolerability for induction chemotherapy. A percutaneous endoscopic gastrostomy (PEG) tube was required in 80 patients, with 10 maintaining PEG use >18 months. Acute grade 4 mucositis and dermatitis developed in 2.0% and 4.0% of patients, respectively. No patient experienced nadir sepsis, grade ≥3 late xerostomia, or significant nephropathy or gastrointestinal toxicity. Median follow-up was 30 months. The 3-year locoregional control rate was 83.2% with disease-free survival and overall survival rates of 78.8% and 76.5%, respectively. CONCLUSION: Rates of acute and late toxicities were low, with excellent radiation dose delivery and impressive tumor control at 3 years, suggesting that concurrent carboplatin and paclitaxel with IMRT is a reasonable therapeutic option for the curative treatment of LAHNC.

Therapeutic hypothermia after exsanguination.

Therapeutic hypothermia has been shown to be effective in out-of-hospital cardiac arrest, and use of this therapy has been expanded to involve in-hospital cardiac arrest. The utility of hypothermia in cardiac arrest after hemorrhage is not known. We describe a case of successful neurological and functional outcome after in-hospital pulseless electrical activity arrest secondary to exsanguination from an internal carotid artery rupture. Therapeutic hypothermia by surface cooling was initiated after acute control of the bleeding source, restoration of circulating blood volume, and hemodynamic stabilization. We believe therapeutic hypothermia use will continue to increase for in-hospital cardiac arrests.

Optimizing Botox regimens in patients with adductor spasmodic dysphonia and essential tremor of voice: A 31-year experience.

Objective: The purpose of this study was to quantitatively compare the effectiveness of unilateral and bilateral botulinum toxin A (BTX-A) injections for mitigating undesirable weak/breathy voice quality and dysphagia for patients with adductor spasmodic dysphonia and/or essential tremor of voice (ETV). Methods: Data were collected from the medical records of 319 patients, yielding three treatment cohorts: patients who received an equal dose bilateral injection regimen (BL=) throughout their course of treatment at VUMC, patients who switched to a unilateral injection regimen (UL), and patients who switched to an unequal dose bilateral injection regimen (BL≠). Changes in length of improvement, duration of weak/breathy voice, and dysphagia severity were compared. Results: The BL = treatment group reported the longest duration of improved voice. Shorter periods of improved voice were reported at baseline by patients who later switched to UL or BL ≠ injection regimens. Patients receiving UL injections reported significantly reduced weak/breathy voice and dysphagia. Patients receiving BL ≠ injections reported increased length of improved voice; however, dysphagia symptoms increased. Ninety-two percent of patients with ETV switched to a UL regimen, with 61% of patients transitioning within the first three injections. Conclusions: Patients with pronounced dysphagia and extended periods of weak/breathy voice may benefit from a UL injection approach to mitigate side effects from BTX-A without sacrificing improved voice outcomes. For patients seeking to extend their length of improved voice, a BL ≠ injection regimen may be effective provided the adverse side effects from BTX-A are minimal. Patients with ETV may benefit from a UL injection approach at the outset of their course of treatment with BTX-A. Level of evidence: III.

Management of postradiation late hemorrhage following treatment for HPV-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Acute oropharyngeal hemorrhage is a serious complication for patients with oropharyngeal squamous cell carcinoma (OPSCC), particularly in patients with a history of radiation therapy (RT). METHODS: Retrospective case series from at a tertiary care center for treated patients with HPV-positive OPSCC presenting with oropharyngeal hemorrhage. RESULTS: Median time from completion of chemoradiation to first hemorrhagic event was 186 days (range 66-1466 days). Seven patients (58%) required intervention to secure their airway. All patients were evaluated for endovascular intervention, six (50%) were embolized. Eight patients (67%) had a second hemorrhagic event; median time to second bleed was 22 days (range 3-90 days). CONCLUSIONS: Acute oropharyngeal hemorrhage is a sequelae following treatment for HPV-positive OPSCC. The majority of bleeds occurred within a year of completion of treatment. While more research is needed to determine optimal treatment paradigms, endovascular intervention should be considered, even if noninvasive imaging does not demonstrate active bleeding.

Hearing impairment in children living with HIV in Haiti.

OBJECTIVE: To identify the prevalence of hearing impairment and associated risk factors in children living with human immunodeficiency virus (HIV) in Haiti. METHODS: A validated smartphone-based platform with pure-tone audiometry was used to screen 341 HIV-infected children for hearing impairment in Port-au-Prince, Haiti from March 2019 to September 2020. If screening was failed, a more comprehensive pure-tone audiometric evaluation was administered. Demographic, otologic, and HIV-related data were obtained through caregiver surveys and medical charts. Statistical analysis included univariate and multivariate logistic regression. RESULTS: Sixty (18%) of 341 HIV-infected children (ages 7-18 years) had hearing impairment. Of those failing their hearing assessment, 17 (28%) had moderate and 5 (8%) had severe or profound hearing loss. Hearing impairment was associated with frequent ear infections (OR 3.37; 95% CI 1.76-6.46; p < 0.001) and family history of hearing loss (OR 5.12; 95% CI 2.14-12.23; p = 0.001) but not viral load (OR 1.00; 95% CI 0.73-1.02; p = 0.28) or antiretroviral therapy duration (OR 0.96; 95% CI 0.79-1.17; p = 0.66). Only 35% of caregivers correctly perceived their child's hearing loss. CONCLUSIONS: Hearing impairment occurs at a higher prevalence in HIV-infected children in Haiti than what is expected for those living without HIV. Frequent ear infections were significantly associated with hearing loss while antiretroviral therapy duration was not. Despite their potential ototoxicity, antiretroviral therapies should be continued and may decrease incidence of otitis media. Low caregiver perception of hearing loss emphasizes the need for routine hearing screening for HIV-infected children.

Evaluation of the Molecular Landscape of Pediatric Thyroid Nodules and Use of a Multigene Genomic Classifier in Children.

Importance: Definitive diagnosis of a thyroid nodule in a child is obtained through diagnostic surgery. This is problematic because pediatric thyroid surgery is associated with higher rates of complications. In adults, preoperative molecular testing improves the management of thyroid nodules, but this has not been validated in children. Objective: To determine whether the molecular landscape of pediatric thyroid nodules is amenable to detection by a multigene genomic classifier (GC) test (ThyroSeq v3; Sonic Healthcare USA). Design, Setting, and Participants: This was a retrospective consecutive case series and GC testing of fine-needle aspiration (FNA) and formalin-fixed paraffin-embedded (FFPE) tissues from sequential pediatric thyroidectomies performed between January 2003 and December 2019 at a single tertiary academic medical center. The study included 95 patients (median [range] age, 16.3 [4.8 to 21.1] years; 75 [79%] female) who underwent surgery for a thyroid nodule. Interventions: A total of 118 thyroid nodule samples (95 FFPE, 23 companion FNAs) yielded informative next-generation sequencing data and multigene GC. Main Outcomes and Measures: The primary outcome was the determination of the pediatric thyroid molecular landscape. The secondary outcome was the diagnostic accuracy of the GC test for pediatric thyroid nodules. Results: Of the 95 patients, 75 (79%) were female, and the median (IQR) age was 16.3 (14.0-17.3) years. Next-generation sequencing confirmed the unique molecular landscape of malignant pediatric thyroid nodules (compared with adults), which is dominated by gene fusions (most commonly RET and NTRK), rare BRAF/RAS alterations, and no TP53 or TERT promoter pathogenic variants. Several poorly differentiated thyroid cancers harbored DICER1 variants. Benign nodules appeared to be almost exclusively associated with TSHR and DICER1 alterations. The test demonstrated a 96% sensitivity (95% CI, 87%-99%) and 78% specificity (95% CI, 64%-88%). The negative predictive value was 95% (95% CI, 88%-98%) and the positive predictive value was 83% (95% CI, 74-89%). The concordance of GC between 23 pairs of matched FFPE and FNA tissues was 96%. Conclusions and Relevance: The study results of this retrospective consecutive case series suggest that the molecular landscape of pediatric nodules is unique but remains amenable to molecular classification. The multigene GC test, with high sensitivity and reasonably high specificity, represents a potential addition to the diagnostic workup of children with thyroid nodules and may decrease the use of diagnostic surgery.