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.

Diffuse Sclerosing Papillary Thyroid Carcinoma: Clinicopathological Characteristics and Prognostic Implications Compared with Classic and Tall Cell Papillary Thyroid Cancer.

BACKGROUND: The clinical behaviour and oncologic outcome of diffuse sclerosing papillary thyroid carcinoma (DS-PTC) is poorly understood. The objectives of this study were to compare the clinicopathological characteristics and oncological outcomes of DS-PTC to classic PTC (cPTC) and tall cell PTC (TC-PTC). METHODS: After institutional review board approval, 86 DS-PTC, 2,080 cPTC, and 701 TC-PTC patients treated at MSKCC between 1986 and 2021 were identified. Clinicopathological characteristics were compared by using chi-square test. Kaplan-Meier and log rank were used to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). DS-PTC patients were propensity matched to cPTC and TC-PTC patients for further comparison. RESULTS: DS-PTC patients were younger with more advanced disease than cPTC and TC-PTC (p < 0.05). Lymphovascular invasion (LVI), extranodal extension, and positive margins were more common in DS-PTC (p < 0.02). Propensity matching confirmed more aggressive histopathological features in DS-PTC. The median number of metastatic lymph nodes was significantly greater and DS-PTC metastases were RAI avid. DS-PTC 5-year RFS was 50.4% compared with 92.4% in cPTC and 88.4% in TC-PTC (p < 0.001). Multivariate analysis confirmed DS-PTC as an independent prognostic factor of recurrence. Ten-year DSS for DS-PTC was 100% compared with 97.1% in cPTC and 91.1% in TC-PTC. Differentiated high-grade, thyroid carcinoma DS had more advanced T-stage and worse 5-year RFS than DS-PTC. CONCLUSIONS: DS-PTC presents with more advanced clinicopathological features than cPTC and TC-PTC. Large-volume nodal metastases and LVI are characteristic features. Almost half of patients develop recurrence despite aggressive initial management. Despite this, with successful salvage surgery DSS is excellent.

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.

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.

Surgical management of pediatric salivary malignant tumors-A single-center cohort study.

BACKGROUND: The purpose of this study was to report incidence, clinicopathologic behavior, management, and outcome of pediatric patients treated surgically for salivary gland (SG) malignancies. METHODS: Patients who underwent surgery for SG malignancies from 1985 to 2015 were identified. Clinical, pathological, treatment and outcomes data were collected. Disease-specific survival (DSS), recurrence-free survival (RFS), and overall survival (OS) were calculated using Kaplan-Meier method. RESULTS: Twenty-eight pediatric patients were included. The most common histopathological types were mucoepidermoid (n = 18, 64.3%), acinic cell (n = 7, 25.0%), adenoid cystic (n = 2, 7.1%), and adenocarcinoma (n = 1, 3.6%). Surgical approach varied and ranged from superficial parotidectomy (n = 11, 39.3%) to partial maxillectomy (n = 6, 21.4%). Nine patients (32%) required postoperative radiotherapy. DSS, OS, and RFS probability at 5 years were 96.4%, 96.4%, and 89.3%, respectively. CONCLUSION: Pediatric SG malignancies are rare and have favorable outcome at 5 years. Larger, multi-institutional studies are required to better understand the natural history of these rare tumors.

Partial Thyroidectomy With Incidental Metastatic Lymph Nodes.

Importance: The need for completion thyroidectomy in patients with incidental metastatic lymph nodes after partial thyroidectomy is unclear. Objective: To investigate the outcomes of patients with incidental metastatic lymph nodes following partial thyroidectomy. Design, Setting, and Participants: A retrospective review of a prospectively maintained thyroid cancer database from 1985 to 2015 was carried out at a head and neck surgery practice at a tertiary referral cancer center. A total of 74 patients who underwent thyroid lobectomy or thyroid isthmusectomy between 1985 and 2015 and were found to have incidental metastatic lymph nodes on final pathologic analysis and were selected to be observed without immediate completion thyroidectomy were included. A separate group of additional 11 patients who underwent immediate completion thyroidectomy was also identified and reviewed. Main Outcome and Measure: Analysis took place from February to May 2022. Recurrence-free survival outcomes of patients found to have incidental metastatic lymph nodes on final pathologic analysis following partial thyroidectomy with no immediate completion thyroidectomy. Results: A total of 74 patients were observed, with a median (IQR) age of 39 (28-49) years; 44 (59%) were women. Sixty-four patients underwent thyroid lobectomy and 10 patients had isthmusectomy. Classic papillary thyroid carcinoma was the most common histologic type (34 [46%]). Vascular invasion and microscopic extrathyroidal extension were present in 11 patients (16%) and 22 patients (30%), respectively. Positive margins were identified in 5 patients (7.8%). Size of metastatic lymph nodes ranged between 0.07 cm and 1.2 cm. No extranodal extension was reported. A total of 52 patients (70%) were classified as intermediate risk for recurrence based on the American Thyroid Association risk stratification system. The median (IQR) follow up was 48.15 (15.4-86.1) months, during which only 1 patient had a regional recurrence. Another patient underwent delayed completion thyroidectomy for a contralateral lobe malignant abnormality. Recurrence-free survival, disease-specific survival, and overall survival were 97.4%, 100%, and 96.2%, respectively. A separate group of 11 patients who underwent immediate completion thyroidectomy were reviewed. These patients were more likely to have tall-cell papillary thyroid carcinoma (6 [55%] vs 13 [18%]), multifocality (9 [82%] vs 28 [41%]), microscopic extrathyroidal extension (8 [73%] vs 22 [30%]), and positive margins (3 [30%] vs 5 [7.8%]) compared with patients who were under observation only. Conclusion and Relevance: Completion thyroidectomy may not be necessary in appropriately selected patients who are found to have incidental metastatic lymph nodes (N1a) after partial thyroidectomy for localized well-differentiated thyroid cancer.

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.

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.

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.

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.

Evaluation of Surgical Margin Status in Patients With Salivary Gland Cancer.

Importance: Salivary gland cancer comprises a diverse group of histologic types with different biological behavior. Owing to this heterogeneity, the association of margin status and postoperative adjuvant radiotherapy has been poorly studied. Objective: To examine the association between surgical margin status and oncologic outcomes and the subsequent outcome of adjuvant radiotherapy in patients with salivary gland carcinomas. Design, Setting, and Participants: This cohort study analyzed data from institutional records at Memorial Sloan Kettering Cancer Center from 1985 to 2015. Statistical analysis was completed on October 31, 2020. After exclusions, 837 patients with surgically treated salivary gland carcinoma were identified. Surgical margins and histologic characteristics identified from pathology reports were recorded, with margins classified as negative, close, and positive, and individual histologic types classified into 3 risk groups: low, intermediate, and high. Exposures: The outcome of adjuvant radiotherapy was determined in patients with close margins with low- and intermediate-risk histologic type and overall pathologic stage I/II disease. Main Outcomes and Measures: Disease-specific survival (DSS) and local recurrence-free survival (LRFS) outcomes were calculated using the Kaplan-Meier method. Multivariable analysis was performed using the Cox proportional hazards regression model. A planned subgroup analysis of patients with close margins was conducted. Results: Among the 837 patients identified, 438 were women (52.3%); median age at surgery was 58 years (range, 6-98). A total of 399 tumors (47.7%) originated from major salivary glands, and 438 (52.3%) from minor salivary glands. Margin positivity rates were not different between minor and major salivary gland tumors. Positive surgical margins were identified in 252 patients (30.1%), with nasal cavity/paranasal sinuses and trachea/larynx subsites as the most common sites. Close margins were recorded in 203 patients (24.3%). Adjuvant radiotherapy was administered in 80.5% (103 of 128) of patients with major salivary gland cancer with positive margins, 58.8% (60 of 102) with close margins, and 30.7% (52 of 169) with negative margins and in 70.2% (87 of 124), 36.6% (37 of 101) , and 19.7% (42 of 213) patients with minor salivary gland cancer. With median follow up time of 57 months (range, 1-363 months), patients with positive margins had poorer DSS and LRFS. However, after controlling for overall stage, histologic risk group, and adjuvant radiotherapy, margin status was not a factor associated with poorer DSS or LRFS. In patients with close margins, low-risk and intermediate-risk histologic type, and overall pathologic stage I/II, patients who did not have adjuvant radiotherapy had comparable local control with those who received adjuvant radiotherapy. Conclusions and Relevance: The findings of this cohort study suggest that patients with salivary gland cancer who have either close or positive surgical margins are at increased risk for poorer local control and survival. After controlling for tumor stage, histologic risk group, and the use of adjuvant radiotherapy, margin status was not an independent factor associated with poorer outcome. Subgroup analyses showed that care for patients with close margins with low-risk or intermediate-risk histologic type who have stage I/II cancers might be managed safely without adjuvant radiotherapy.