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.

Papillary thyroid carcinoma tall cell subtype (PTC-TC) and high-grade differentiated thyroid carcinoma tall cell phenotype (HGDTC-TC) have different clinical behaviour: a retrospective study of 1456 patients.

AIMS: Papillary thyroid carcinoma, tall cell subtype (PTC-TC) is a potentially aggressive histotype. The latest World Health Organisation (WHO) classification introduced a novel class of tumours; namely, high-grade differentiated thyroid carcinoma (HGDTC), characterised by elevated mitotic count and/or necrosis, which can exhibit a tall cell phenotype (HGDTC-TC). METHODS AND RESULTS: We analysed the clinical outcomes in a large retrospective cohort of 1456 consecutive thyroid carcinomas with a tall cell phenotype, including PTC-TC and HGDTC-TC. HGDTC-TC is uncommon, accounting for 5.3% (77 of 1379) of carcinomas with tall cell morphology. HGDTC-TC was associated with significantly older age, larger tumour size, angioinvasion, gross extrathyroidal extension, higher AJCC pT stage, positive resection margin and nodal metastasis (P < 0.05). Compared with PTC-TC, HGDTC was associated with a significantly decreased DSS, LRDFS and distant metastasis-free survival (DMFS; P < 0.001). The 10-year DSS was 72 and 99%, the 10-year LRDFS was 61 and 92% and the 10-year DMFS was 53 and 97%, respectively, for HGDTC-TC and PTC-TC. On multivariate analysis, the classification (HGDTC-TC versus PTC-TC) was an independent adverse prognostic factor for DSS, LRDF, and DMFS when adjusted for sex, age, angioinvasion, margin status, AJCC pT and pN stage. CONCLUSIONS: Compared with PTC-TC, HGDTC-TC is associated with adverse clinicopathological features, a higher frequency of TERT promoter mutations (59% in HGDTC-TC versus 34% in PTC-TC) and incurs a significantly worse prognosis. HGDTC-TC is an independent prognostic factor for carcinoma with tall cell morphology. This validates the concept of HGDTC and the importance of tumour necrosis and high mitotic count for accurate diagnosis and prognosis of differentiated thyroid carcinomas.

Active surveillance for micropapillary thyroid carcinoma: a clinical review.

With the rapid rise in the incidence of micropapillary carcinoma, there is increasing concern about its overdiagnosis and overtreatment. There is considerable interest in managing patients with micropapillary carcinoma with active surveillance or deferred intervention. Various institutions around the world are practicing active surveillance. The major question remains as to who the ideal candidates are and how best to monitor these patients. This clinical review will discuss the ideal, appropriate, and inappropriate patients for active surveillance. It will also discuss the follow-up strategy for these patients and some of the adverse clinical features that will be used to decide against active surveillance. There are uncertainties as to who should be offered active surveillance. Various studies have shown approximately 10% of the patients switching to surgery primarily related to fear factor rather than increase in the tumor size or lymph node metastasis. The results of immediate surgery do raise issues related to complications of thyroid surgery and quality of life. The most ideal candidate would be patients with a tumor below 1 cm, intrathyroidal. For the patient who is a minimalist, the follow up strategy includes, ultrasound every 6 months for the first 1 or 2 years, and then every year after that. If there is a substantial change in the tumor volume or nodal metastasis, surgery should be considered, which happens in less than 10 percent of patients according to many studies. Based on existing literature and clinical experience, it appears that active surveillance is an appropriate strategy for monitoring micropapillary carcinoma.

RAS-Mutated Cytologically Indeterminate Thyroid Nodules: Prevalence of Malignancy and Behavior Under Active Surveillance.

Background: Genomic profiling is now available for risk stratification of cytologically indeterminate thyroid nodules (ITNs). Mutations in RAS genes (HRAS, NRAS, KRAS) are found in both benign and malignant thyroid nodules, although isolated RAS mutations are rarely associated with aggressive tumors. Because the long-term behavior of RAS-mutant ITNs is not well understood, most undergo immediate surgery. In this multicenter retrospective cohort study, we characterize tumor growth kinetics of RAS-mutant ITNs followed with active surveillance (AS) using serial ultrasound (US) scans and examine the histopathologic diagnoses of those surgically resected. Methods: US and histopathologic data were analyzed retrospectively from two cohorts: (1) RAS-mutant ITNs managed with AS at three institutions (2010-2023) and (2) RAS-mutant ITNs managed with immediate surgery at two institutions (2016-2020). AS cohort subjects had ≥3 months of follow-up and two or more US scans. Cumulative incidence of nodule growth was determined by the Kaplan-Meier method and growth by ≥72% change in tumor volume. Pathological diagnoses for the immediate surgery cohort were analyzed separately. Results: Sixty-two patients with 63 RAS-mutated ITNs under AS had a median diameter of 1.7 cm (interquartile range [IQR] 1.2-2.6) at time of diagnosis. During a median AS period of 23 months (IQR 9.5-53.5 months), growth was observed in 12 of 63 nodules (19.0%), with a cumulative incidence of 1.9% (1 year), 23.0% (3 years), and 28.0% (5 years). Most nodules (81.0%) demonstrated stability. Surgery was ultimately performed in 6 nodules, of which 1 (16.7%) was malignant. In the cohort of 209 RAS-mutant ITNs triaged to immediate surgery, 33% were malignant (23.9% American Thyroid Association [ATA] low-risk cancers, 7.2% ATA intermediate-risk, and 1.9% ATA high-risk. During a median follow-up of 6.9 (IQR 4.4-7.1) years, there were no disease-specific deaths in these patients. Conclusions: We describe the behavior of RAS-mutant ITNs under AS and find that most demonstrate stability over time. Of the resected RAS-mutant nodules, most were benign; of the cancers, most were ATA low-risk. Immediate surgical resection of all RAS-mutant ITNs appears to be a low-value practice. Further research is needed to help define cases most appropriate for AS or immediate surgery.

Association of the Genomic Profile of Medullary Thyroid Carcinoma with Tumor Characteristics and Clinical Outcomes in an International Multicenter Study.

Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.

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.

Thyroglobulin and thyroglobulin antibody: an updated clinical and laboratory expert consensus.

OBJECTIVE: Thyroglobulin measurement is the cornerstone of modern management of differentiated thyroid cancer, with clinical decisions on treatment and follow-up based on the results of such measurements. However, numerous factors need to be considered regarding measurement with and interpretation of thyroglobulin assay results. DESIGN: The present document provides an integrated update to the 2013 and 2014 separate clinical position papers of our group on these issues. METHODS: Issues concerning analytical and clinical aspects of highly-sensitive thyroglobulin measurement will be reviewed and discussed based on an extensive analysis of the available literature. RESULTS: Thyroglobulin measurement remains a highly complex process with many pitfalls and major sources of interference, especially anti-thyroglobulin antibodies, need to be assessed, considered and, when necessary, dealt with appropriately. CONCLUSIONS: Our expert consensus group formulated 53 practical, graded recommendations for guidance on highly-sensitive thyroglobulin and TgAb in laboratory and clinical practice, especially valuable where current guidelines do not offer sufficient guidance.

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.

The use of single-timepoint images to link administered radioiodine activity (MBq) to a prescribed lesion radiation-absorbed dose (cGy): a regression-based prediction interval tool for the management of well-differentiated thyroid cancer patients.

PURPOSE: To introduce a biomarker-based dosimetry method for the rational selection of a treatment activity for patients undergoing radioactive iodine 131I therapy (RAI) for metastatic differentiated thyroid cancer (mDTC) based on single-timepoint imaging of individual lesion uptake by 124I PET. METHODS: Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUVmax > 1 underwent quantitative PET scans at 24, 48, 72, and 120 h post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion radiation-absorbed dose. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion radiation dose metrics, with candidate biomarkers ("predictors") such as SUVmax and activity in microcurie per gram, from a single imaging timepoint. RESULTS: In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming wide heterogeneity of lesion radiation dose. Initial findings from the prediction curve on all 208 lesions confirmed that a 48-h SUVmax was the best predictor of lesion radiation dose and permitted calculation of the 131I activity required to achieve a lesional threshold radiation dose (2000 cGy) within defined confidence intervals. CONCLUSIONS: Based on MIRD lesion-absorbed dose estimates and regression statistics, we report on the feasibility of a new single-timepoint 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. The approach provides clinicians with a tool to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed dose (cGy) for selected index lesions based on a single 48-h measurement 124I-PET image, provided the selected activity does not exceed the maximum tolerated activity (MTA) of < 2 Gy to blood, as is standard of care at Memorial Sloan Kettering Cancer Center. TRIAL REGISTRATION: NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.

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.

Large (>4 cm) Intrathyroidal Encapsulated Well-Differentiated Follicular Cell-Derived Carcinoma Without Vascular Invasion May Have Negligible Risk of Recurrence Even When Treated with Lobectomy Alone.

Background: Thyroid carcinoma >4 cm in size is staged as T3a. The current American Thyroid Association guidelines recommend subtotal/total thyroidectomy and consideration for postoperative radioactive iodine (RAI) treatment for these tumors. In this retrospective cohort study, we aimed to explore the clinical course of large encapsulated thyroid carcinoma without other risk factors. Methods: Eighty-eight patients with large (>4 cm) encapsulated well-differentiated thyroid carcinoma resected between 1995 and 2021 were included in this retrospective cohort study. Exclusion criteria were tall cell variant, any extent of vascular invasion, extrathyroidal extension (microscopic or gross), high-grade histology, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), infiltrative tumors, positive resection margin, and cases with follow-up <1 year. The primary outcomes are risk of nodal metastasis at the initial resection, disease-free survival (DFS), and disease-specific survival (DSS). Results: The tumor histotype was follicular carcinoma (n = 18, 21%), oncocytic (Hurthle cell) carcinoma (n = 8, 9%), and papillary thyroid carcinoma (PTC; n = 62, 70%). Among PTC, 38 were encapsulated follicular variant, 20 classic type, and 4 solid variant. Four cases had extensive capsular invasion (CI), 61 (69%) had focal CI, whereas 23 did not have CI. Thirty-two cases (36%) were treated with lobectomy/hemithyroidectomy alone, and 55 patients (62%) did not receive RAI. Five patients had nodal metastasis at the time of primary resection, all of whom had classic-type PTC. The median follow-up period was 4.8 years (interquartile range: 3.2-9.7 years). No recurrence, being local, regional, or distant, was observed in the entire cohort, including those patients treated with lobectomy alone without RAI. The 10-year DFS and DSS were 100%, respectively. Conclusion: Large intrathyroidal encapsulated well-differentiated thyroid carcinoma without vascular invasion follow an extremely indolent clinical course with negligible risk of recurrence. Lobectomy alone without RAI may be the appropriate treatment strategy for this selected group of patients.

Percutaneous ablation of low-risk papillary thyroid cancer.

Abstract: Minimalistic management options such as active surveillance and thyroid lobectomy are increasingly being accepted as reasonable management options for properly selected patients with low-risk papillary thyroid cancer. Leveraging technologies developed for the treatment of benign thyroid nodules, ultrasound-guided percutaneous thermal ablation is now being evaluated as a potential additional minimalistic management option for small, intrathyroidal, low-risk papillary thyroid cancer. Published retrospective data on more than 5000 low-risk papillary thyroid cancer patients treated with thermal ablation indicate that with appropriate training and proper patient selection, these technologies can be safely and effectively applied to papillary microcarcinomas. When compared to immediate surgery, thermal ablation appears to have lower complication rates with similar short-term rates of recurrence. Proper patient selection is facilitated by the use of a clinical framework which integrates imaging characteristics, patient characteristics, and medical team characteristics to classify a patient as ideal, appropriate, or inappropriate for minimalistic management options (active surveillance, thyroid lobectomy, or thermal ablation). While retrospective in nature and lacking randomized prospective clinical trial data, currently available data do support the proposition that thermal ablation technologies reliably destroy papillary thyroid microcarcinoma lesions and are associated with clinically acceptable oncologic outcomes when done by experienced teams in properly selected patients.

Surgical management of T1/T2 node-negative papillary thyroid cancer with tall cell histology: Is lobectomy enough?

BACKGROUND: The tall cell variant of papillary thyroid carcinoma has traditionally been treated more aggressively than classic papillary thyroid carcinoma. However, this may not be justified in patients with T1/T2 tall cell variant node-negative tumors. METHODS: We evaluated well-differentiated thyroid cancers treated surgically between 1985 and 2015 at our institution. We compared patients undergoing lobectomy for node-negative T1/T2 tall cell variant tumors with the same cohort with classic papillary thyroid carcinoma. Patients who underwent early planned completion thyroidectomy were excluded. Tall cell variant tumors were defined as those with ≥30% tall cells. Survival and recurrence outcomes were determined by the Kaplan-Meier method and groups compared using the log-rank test. RESULTS: Thyroid lobectomy was performed for T1/T2 N0X disease in 70 (15%) tall cell cases and 429 (23%) classic papillary thyroid carcinoma cases. There was no significant difference in 10-year overall survival (P = .56) or locoregional recurrence-free probability (P = .52). Disease-specific survival and local or central nodal recurrence-free probability were 100% in both groups. In 9 papillary thyroid carcinoma cases, subsequent contralateral lobe tumors developed, and in 5, lateral neck metastases developed. No recurrences were seen in the tall cell group. CONCLUSION: T1 node-negative tumors with tall cell histology can be satisfactorily managed with thyroid lobectomy, with equivalent oncological outcomes to classic papillary thyroid carcinoma.

Outcomes and Toxicities of Nonmedullary Thyroid Tumors Treated with Proton Beam Radiation Therapy.

Purpose: Proton therapy is an emerging therapy for several malignancies owing to its favorable therapeutic ratio. There are very limited data on the use of proton therapy in the management of thyroid carcinoma. Our objective was to review the safety, feasibility, and outcomes of proton therapy for patients with thyroid cancer treated to the head and neck. Methods: From our institution's proton database from 2012 to 2021, we identified 22 patients with thyroid cancer treated with proton beam therapy. We evaluated outcomes and toxicities. Results: Median follow-up was 26 months. Of the 22 patients, 50% were female. The mean age was 65 years. Three patients had anaplastic cancer; 13, papillary carcinoma; 2, follicular carcinoma; and 2, poorly differentiated carcinoma. Forty-six percent had T4 disease. Primary targets were the central neck compartment, level VI, and upper mediastinum. Radiation dose was 60 GyRBE adjuvantly, and 70 GyRBE for gross disease (range, 6000-7600 GyRBE). Eight patients underwent upfront adjuvant radiation, and 3 received definitive radiation for unresectable disease upfront. Eleven patients received either salvage or palliative radiation. Fifty-nine percent of patients had extrathyroidal extension, and 64% of patients had gross disease in the neck before treatment. Fifty percent of patients had metastatic disease before treatment. Sixteen patients received concurrent chemotherapy, 63% of these patients received doxorubicin. For all patients, 1-year local regional recurrence (LRR) was 0%, and overall survival (OS) was 90%. Acute grade 3+ toxicities occurred in 27% of patients, the most frequent being dermatitis (27%). Three patients required a percutaneous endoscopic gastrostomy tube after radiation therapy (RT), 2 owing to progression. There were no grade 4+ toxicities. Conclusions: Proton therapy for thyroid cancer appears feasible and effective with minimal toxicities. Prospective studies comparing proton therapy with intensity-modulated RT, to evaluate the clinical efficacy of using proton therapy to reduce toxicities in patients undergoing radiation for thyroid cancer, are warranted.

Tumor Grade Predicts for Calcitonin Doubling Times and Disease-Specific Outcomes After Resection of Medullary Thyroid Carcinoma.

Background: Tumor grade is a new validated prognostic factor for medullary thyroid cancer (MTC). Calcitonin doubling time can predict MTC recurrence. We aimed to describe the association of tumor grade with calcitonin doubling and its effect on disease-specific outcomes times after resection. Methods: A retrospective analysis of MTC patients who underwent resection at a single tertiary-care cancer center between 1986 and 2017 were evaluated. Tumors were designated as high-grade MTC if two head and neck pathologists identified mitotic index ≥5 per 2 mm2, tumor necrosis, or a Ki67 proliferative index ≥5% within the tumor. Calcitonin doubling time was calculated using a validated calculator with at least three consecutive levels. Using Cox proportional hazards models, outcomes evaluated included locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: Among 117 patients, 95 were low grade and 22 high grade. Median follow-up was 70.2 months. High-grade patients demonstrated significantly faster calcitonin doubling times when compared with low-grade patients (8.51 ± 3.22 months vs. 38.42 ± 11.19 months; p < 0.001). In addition, most high-grade patients (66.7%) had calcitonin doubling times less than 1 year compared with fewer low-grade patients (1.0%; p < 0.001). High- and low-grade patients were further stratified by those who had calcitonin doubling times less than or greater than 2 years-a previously validated prognostic cutoff point. For patients with calcitonin doubling times less than 2 years, 70% were high grade, while 30% were low grade (p < 0.001). On multivariate analysis comparing grade and calcitonin doubling times, high-grade patients had significantly worse LRFS (hazards ratio [HR] 4.77 [confidence interval; CI 1.19-8.81]), DMFS (HR 7.25 [CI 2.36-22.28]), and OS (HR 6.04 [CI 1.85-19.72]; p < 0.05 for all), while calcitonin doubling times less than 2 years had worse DMFS (HR 7.22 [CI 1.05-49.75]). High-grade patients with calcitonin doubling times less than 2 years had associated worse LRFS and OS (both p < 0.05) compared with low-grade patients. Conclusions: The majority of high-grade MTC patients have calcitonin doubling times less than 2years. Close monitoring should be advocated for patients assessed to have high-grade tumors as they are at risk for poor disease-specific outcomes and structural recurrence.