Pediatric Medullary Thyroid Carcinoma: Clinical Presentations and Long-term Outcomes in 144 Patients Over Six Decades.

CONTEXT: Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. OBJECTIVE: To describe the clinical presentations and long-term outcomes of a large cohort of children and young adults with sMTC compared with hereditary MTC (hMTC). METHODS: Retrospective study of 144 patients diagnosed with MTC between 1961-2019 at an age ≤21 years and evaluated at a tertiary referral center. RESULTS: In contrast to hMTC (n=124/144, 86%), patients with sMTC (n=20/144, 14%) are older (p<0.0001), have larger tumors (p<0.0001), a higher initial stage grouping (p=0.001) and have more structural disease (p=0.0045) and distant metastases (DM) (p=0.00084) at last follow up, but are not more likely to die from MTC (p=0.42). Among 77 patients diagnosed clinically, not by family history (20/20 sMTC and 57/124 hMTC), there was no difference in the initial stage (p=0.27), presence of DM at diagnosis (p=1.0), disease status at last follow-up (p=0.13), overall survival (p=0.57), or disease specific survival (p=0.87). Of the twelve sMTC tumors that underwent somatic testing, eleven (91%) had an identifiable alteration: ten RET gene alterations and one ALK fusion. CONCLUSIONS: sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy.

Endocrine surgery in the Coronavirus disease 2019 pandemic: Surgical Triage Guidelines.

BACKGROUND: In the face of the COVID-19 pandemic, cancer care has had to adapt rapidly given the Centers for Disease Control and Prevention and the American College of Surgeons (ACS) issuing recommendations to postpone nonurgent surgeries. METHODS: An institutional multidisciplinary group of Head and Neck Surgical Oncology, Surgical Endocrinology, and Medical Endocrinology devised Surgical Triaging Guidelines for Endocrine Surgery during COVID-19, aligned with phases of care published by the ACS. RESULTS: Phases of care with examples of corresponding endocrine cases are outlined. Most cases can be safely postponed with active surveillance, including most differentiated and medullary thyroid cancers. During the most acute phase, all endocrine surgeries are deferred, except thyroid tumors requiring acute airway management. CONCLUSIONS: These guidelines provide context for endocrine surgery within the spectrum of surgical oncology, with the goal of optimal individualized multidisciplinary patient care and the expectation of significant resource diversion to care for patients with COVID-19.

Facilitating anaplastic thyroid cancer specialized treatment: A model for improving access to multidisciplinary care for patients with anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a highly aggressive thyroid cancer. Several treatment trials are available, but the number of eligible patients to participate is very low because of the rarity and aggressiveness of the disease. METHODS: Facilitating Anaplastic Thyroid Cancer Specialized Treatment (FAST) is a quality improvement project aimed at decreasing time from referral to disposition (scheduling of first appointment) to our institution. After identifying reasons for delays, we created a new process flow specifically for patients with ATC allowing patients to be scheduled immediately. RESULTS: Historical data revealed a mean referral to disposition time for patients with ATC of 8.7 days before our intervention. After the intervention, the mean referral to disposition time was reduced to 0.5 days. Participation in treatment trials for all patients with ATC was 34%. CONCLUSION: Since the implementation of FAST, the access time has decreased and the number of successful referrals for ATC has increased significantly.

Bone Metastases and Skeletal-Related Events in Medullary Thyroid Carcinoma.

CONTEXT: Bone metastases (BM) can lead to devastating skeletal-related events (SREs) in cancer patients. Data regarding medullary thyroid carcinoma (MTC) with BM are lacking. OBJECTIVE: We evaluated the natural history of BM and SREs in MTC patients identified by a cancer center tumor registry. SETTING: The study was conducted at a tertiary cancer center. PATIENTS AND MAIN OUTCOME MEASURES: We retrospectively reviewed the charts of MTC patients with BM who received care from 1991 to 2014 to characterize BM and SREs. RESULTS: Of 1008 MTC patients treated, 188 were confirmed to have BM (19%), of whom 89% (168 of 188) had nonosseous distant metastases. Median time from MTC to BM diagnosis was 30.9 months (range 0-533 mo); 25% (45 of 180) had BM identified within 3 months of MTC diagnosis. Median follow-up after detecting BM was 1.6 years (range 0-23.2 y). Most patients (77%) had six or more BM lesions, most often affecting the spine (92%) and pelvis (69%). Many patients (90 of 188, 48%) experienced one or more SREs, most commonly radiotherapy (67 of 90, 74%) followed by pathological fracture (21 of 90, 23%). Only three patients had spinal cord compression. Patients with more than 10 BM lesions were more likely to experience SREs (odds ratio 2.4; P = .007), with no difference in 5-year mortality after MTC diagnosis between patients with (31%) and without SREs (23%) (P = .11). CONCLUSIONS: In this large retrospective series, BM in MTC was multifocal, primarily involving the spine and pelvis, supporting screening these regions for metastases in at-risk patients. SREs were common but spinal cord compression was rare. Antiresorptive therapies in this population should be investigated further with prospective trials.

Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience.

CONTEXT: Vemurafenib, a selective BRAF inhibitor, appears to have promising clinical activity in patients with papillary thyroid cancer (PTC) harboring the BRAF(V600E) mutation. OBJECTIVE: To determine the efficacy and safety of vemurafenib when used outside of a clinical trial. DESIGN: A retrospective review at MD Anderson Cancer Center. METHODS: The best responses were evaluated using RECIST v1.1. A single radiologist reviewed all images. Adverse events (AEs) were evaluated using CTCAE v.4.0. RESULTS: We identified 17 patients with advanced PTC harboring the BRAF(V600E) mutation who were treated with vemurafenib outside of a clinical trial. Median age at diagnosis was 63 years, and 53% were male. At vemurafenib start, 3 (18%) patients had disease confined to the neck, and 14 (72%) had distant metastases. Tyrosine kinase inhibitors had been previously administered to 4 (24%) patients. Two (12%) patients discontinued vemurafenib because of AEs before restaging. Best response: partial response (PR) in 7/15 (47%) and stable disease (SD) in 8/15(53%) patients. The rate of durable response (PR plus SD ≥ 6 months) was 67%. Median time to treatment failure was 13 months. There was no association between change in thyroglobulin and tumor size. Drug discontinuation, drug interruptions, and dose reductions were needed in 5 (29%), 13 (76%), and 10 (59%) patients, respectively. Most common AEs were fatigue (71%), weight loss (71%), anorexia (65%), arthralgias (59%), hair loss (59%), rash (59%), hand-foot syndrome (53%), calluses (47%), diarrhea (47%), fever (41%), dry mouth (35%), nausea (35%), and verrucous keratosis (35%). Grade ≥ 3 AEs were present in 8 (47%) patients. CONCLUSIONS: Vemurafenib is a potentially effective and well-tolerated treatment strategy in patients with advanced PTC harboring the BRAF(V600E) mutation. Our results are similar to those reported in a phase II clinical trial and support the potential role of vemurafenib in this patient population.

Update on medullary thyroid cancer.

Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer, demonstrating variable behavior from indolent disease to highly aggressive, progressive disease. There are distinguishing phenotypic features of sporadic and hereditary MTC. Activation or overexpression of cell surface receptors and up-regulation of intracellular signaling pathways in hereditary and sporadic MTC are involved in the disease pathogenesis. There has been an exponential rise in clinical trials with investigational agents, leading to approval of 2 medications for progressive, advanced MTC. Developments in understanding the pathogenesis of MTC will hopefully lead to more effective and less toxic treatments of this rare but difficult to treat cancer.

Efficacy and tolerability of different starting doses of sorafenib in patients with differentiated thyroid cancer.

Sorafenib has proven efficacy in advanced differentiated thyroid cancer (DTC), but many patients must reduce the dose or discontinue treatment because of toxicity. The tolerability and efficacy of lower starting doses of sorafenib for DTC remain largely unstudied. Methods. We retrospectively examined overall survival, time to treatment failure, time to progression, discontinuation rates, and dose-reduction and interruption rates in patients with metastatic DTC treated with first-line sorafenib outside of a clinical trial. Two patient groups were compared; group 1 received the standard starting dose of 800 mg/day, and group 2 received any dose lower than 800 mg/day. Results. We included 75 adult patients, with 51 in group 1 and 24 in group 2. Mean age at diagnosis was 54 years, and 56% were male. The most common histologies included 43% papillary thyroid cancer of the conventional type, 15% papillary thyroid cancer of the follicular variant, and 15% Hürthle cell carcinoma. Time to treatment failure was 10 months (95% confidence interval [CI]: 5.6-14.3) in group 1 and 8 months (95% CI: 3.4-12.5) in group 2 (p = .56). Median overall survival was 56 months (95% CI: 30.6-81.3) in group 1 and 30 months (95% CI: 16.1-43.8) in group 2 (p = .08). Rates of discontinuation due to disease progression were 79% in group 1 and 91% in group 2, and 21% in group 1 and 9% in group 2 (p = .304) stopped treatment because of toxicity. Dose-reduction rates were 59% and 43% (p = .29), and interruption rates were 65% and 67% (p = .908) in group 1 and group 2, respectively. Conclusion. Efficacy and tolerability of sorafenib in treatment-naïve DTC patients does not appear to be negatively influenced by lower starting daily doses.

Role of salvage targeted therapy in differentiated thyroid cancer patients who failed first-line sorafenib.

CONTEXT: Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE: The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN: This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS: The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES: Progression-free survival, best response, and median OS were measured. RESULTS: Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS: Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Does laparoscopic adrenalectomy jeopardize oncologic outcomes for patients with adrenocortical carcinoma?

BACKGROUND: For patients with known or suspected adrenocortical carcinoma (ACC), considerable controversy exists over the use of laparoscopic adrenalectomy. The purpose of this study was to assess recurrence and survival patterns in patients with a pathologic diagnosis of ACC treated with laparoscopic versus open adrenalectomy. METHODS: All patients referred to our center with a diagnosis of ACC from April 1, 1993 to May 1, 2012 were reviewed. Three groups of patients were compared: patients referred after laparoscopic resection elsewhere, patients referred after open resection elsewhere, and patients treated primarily at our center (all resected by the open approach). Clinical factors and overall, recurrence-free, and peritoneal recurrence-free survivals were compared between groups. RESULTS: During the study period, 46 patients presented after laparoscopic resection at an outside institution, 210 patients after open resection at an outside institution, and 46 patients were treated at our institution with open resection. Despite a smaller tumor size, patients treated laparoscopically developed peritoneal carcinomatosis more frequently compared to those treated with an open approach (p = 0.006 for number with peritoneal recurrence). When controlling for tumor stage, open-approach patients experienced superior recurrence-free and overall survival. CONCLUSION: Despite typically being performed in patients with smaller tumors, laparoscopic adrenalectomy for ACC is associated with higher rates of recurrence, particularly peritoneal recurrence. For patients with known or suspected ACC, the oncologic benefits of open resection outweigh the short-term benefits of minimally invasive surgery.

Ultrasonography should not guide the timing of thyroidectomy in pediatric patients diagnosed with multiple endocrine neoplasia syndrome 2A through genetic screening.

BACKGROUND: American Thyroid Association (ATA) guidelines suggest that thyroidectomy can be delayed in some children with multiple endocrine neoplasia syndrome 2A (MEN2A) if serum calcitonin (Ct) and neck ultrasonography (US) are normal. We hypothesized that normal US would not exclude a final pathology diagnosis of medullary thyroid cancer (MTC). METHODS: We retrospectively queried a MEN2A database for patients aged<18 years, diagnosed through genetic screening, who underwent preoperative US and thyroidectomy at our institution, comparing preoperative US and Ct results with pathologic findings. RESULTS: 35 eligible patients underwent surgery at median age of 6.3 (range 3.0-13.8) years. Mean MTC size was 2.9 (range 0.5-6.0) mm. The sensitivity of a US lesion≥5 mm in predicting MTC was 13% [95% confidence interval (CI) 2%, 40%], and the specificity was 95% [95% CI 75%, 100%]. Elevated Ct predicted MTC in 13/15 patients (sensitivity 87% [95% CI 60%, 98%], specificity 35% [95% CI 15%, 59%]). The area under the receiver operating characteristic curve (AUC) for using US lesion of any size to predict MTC was 0.50 [95% CI 0.33, 0.66], suggesting that US size has poor ability to discriminate MTC from non-MTC cases. The AUC for Ct level at 0.65 [95% CI 0.46, 0.85] was better than that of US but not age [AUC 0.62, 95% CI 0.42, 0.82]. CONCLUSIONS: In asymptomatic children with MEN2A diagnosed by genetic screening, preoperative thyroid US was not sensitive in identifying MTC of any size and, when determining the age for surgery, should not be used to predict microscopic MTC.

Long-term follow-up data may help manage patient and parent expectations for pediatric patients undergoing thyroidectomy.

BACKGROUND: We investigated the incidence and impact of postoperative complications in children who underwent total thyroidectomy (TTx). METHODS: The records of all pediatric patients undergoing TTx (2001-2011) at our institution were retrospectively reviewed for the occurrence of biochemical hypothyroidism (thyroid-stimulating hormone >10 mIU/mL), laboratory assessments, and medication nonadherence. RESULTS: The 74 patients (median age, 12.5 years) had thyroid cancer (differentiated, n = 39; medullary, n = 16) or benign pathology (n = 19; 16 with multiple endocrine neoplasia type 2A). The median postoperative follow-up was 3.2 years; 46 patients (62%) had ≥ 1 year follow-up. Forty-one percent had ≥ 1 period of medication nonadherence; this was not associated with age at TTx (P = .30). Non-treatment-related hypothyroidism occurred in 33% of patients during postoperative year (POY) 1. The number of POY1 laboratory assessments among the 30% of patients with parathyroid dysfunction was more than twice that among patients with normal parathyroid function (median assessments per year 8 vs 3; P < .0001). Forty-four percent of patients/families reported behavioral or physiologic changes; 40% were concomitant with abnormal thyroid function. CONCLUSION: More than 40% of pediatric patients were unable to fully adhere to postoperative medication regimens, and non-treatment-related hypothyroidism was common. Postoperative hypoparathyroidism doubled the number of laboratory assessments obtained. These data may help families better prepare for TTx sequelae.

Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience.

BACKGROUND: Cushing syndrome (CS) secondary to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) has been described in association with a variety of tumors. The current experience with this syndrome was based on a few case series and individual case reports. Limited data were available about the tumors associated with CS-EAS in a cancer center setting. In this report, the authors have described their experience with CS-EAS at The University of Texas MD Anderson Cancer Center to further enhance the current understanding and management of this syndrome. METHODS: This was a retrospective review of 43 patients with CS-EAS who were diagnosed between 1979 and 2009 at The University of Texas MD Anderson Cancer Center. RESULTS: Different neuroendocrine tumors were associated with CS-EAS. Twenty-one patients (48.9%) had tumors located in the chest cavity, with bronchial carcinoid and small cell lung cancer representing the 2 most common causes. The ACTH source remained occult in 4 patients (9.3%) despite extensive workup. Clinical presentation varied, and the classic features of CS were not evident in some patients. Death occurred in 27 patients (62.8%), and the median overall survival was 32.2 months. Major morbidities included new-onset or worsening hyperglycemia (77%), symptomatic venous thromboembolism (14%), and infections (23%). CONCLUSIONS: In patients with CS-EAS who attended a comprehensive cancer center, tumors originating in the chest cavity were the leading tumors associated with this syndrome. The authors suspect that CS-EAS is under reported because of the atypical presentation in some patients. Thus, they suggest careful evaluation of patients with neuroendocrine tumors to avoid missing coexisting CS-EAS.

Predictors of direct costs of diabetes care in pediatric patients with type 1 diabetes.

OBJECTIVE: This study examines factors that predict elevated direct costs of pediatric patients with type 1 diabetes. METHODS: A cohort of 784 children with type 1 diabetes at least 6 months postdiagnosis and managed by pediatric endocrinologists at Texas Children's Hospital were included in this study. Actual reimbursed costs from January 2004 to December 2005 were obtained. Medication and supply costs were based on estimates from insulin dosage and type of insulin regimen prescribed, respectively. We examined utilization of care, total diabetes-related direct medical costs, and predictors of direct costs and hospitalization. RESULTS: Annually, 7% (58/784) of patients (excluding initial hospitalization at diagnosis) had a diabetes-related hospitalization and median length of stay was days. Mean total diabetes-related direct cost per person-year was $4730 [95% confidence interval (CI), 4516-4944]. Supplies accounted for 38% and medications 33% of costs, respectively. Older age, hemoglobin A(1C) (HbA(1C) ) > 8.5%, use of a multi-injection or pump regimen, living in a non-married household, and female gender were associated with higher annual costs. HbA(1C) > 8.5%, living in a non-married household, and female gender increased the odds of a diabetes-related hospitalization. DISCUSSION: Better metabolic control in patients with type 1 diabetes was associated with lower direct medical costs and lower odds of hospitalization. Marital status of the primary caregiver, irrespective of type of insurance, impacts the patient's healthcare costs and risk of hospitalization. This large single-center US study analyzes cost distribution in children with diabetes and is informative for payers and providers focused on effective management and improving healthcare costs.

Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation.

BACKGROUND: Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation. SUMMARY: The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the woman and her three children (3-5 years old) had the RET-A883F mutation. The children had near-normal calcitonin levels, and none had sonographic evidence of suspicious thyroid nodules or cervical lymphadenopathy. CONCLUSION: A family with MEN-2B due to RET-A883F mutation displayed a less aggressive form of MTC than what is usually seen in patients with RET-M918T mutation. RET-A883F mutation could be a lower-risk mutation than previously thought and the current recommendation of prophylactic thyroidectomy in the first year of life may not be warranted. Further reports will help clarify the natural history of MTC caused by this mutation.

Do the recent American Thyroid Association (ATA) Guidelines accurately guide the timing of prophylactic thyroidectomy in MEN2A?

BACKGROUND: In 2009, the American Thyroid Association (ATA) published consensus guidelines for timing of prophylactic thyroidectomy (PrThy) for treatment of hereditary medullary thyroid cancer (MTC). The aim of this study was to assess whether the clinical guidelines outlined in the ATA recommendations added to the specific mutation risk level could predict the presence of MTC on final pathology. METHODS: A retrospective study was performed of patients undergoing PrThy. We evaluated mutation-based risk levels in combination with 2009 ATA guidelines for resection. RESULTS: Overall, 54 patients underwent PrThy between 1972 and 2009. The median age at PrThy was 11.5 years (range, 2-68). Only 4 patients (8%) underwent PrThy prior to age 5 years. Most patients with MTC (16/22, 73%) had a level C mutation, and the youngest age of MTC in a level C mutation carrier was 5 years. The youngest age of MTC in level A or B carriers was 15 years. The single factor that predicted an overall decreased risk of MTC at the time of PrThy was meeting all ATA mutation-based postponement guidelines for surgical intervention (P = .04). CONCLUSION: ATA guidelines that includes risk assessment of RET mutation are important in predicting the presence of MTC in patients who are candidates for prophylactic thyroidectomy and in determining the timing of operative resection.

Thyroid cancer in young adults.

The incidence of thyroid cancer in young adults is rising. Differentiated carcinoma (ie, papillary, follicular, and their variants) and medullary thyroid carcinoma (MTC) represent the two most common subtypes, with differing etiologies, prognoses, and management strategies. Ultrasound (US)-guided fine needle aspiration (FNA) is the best initial test for evaluating a nodule or mass suspicious for malignancy. Tumor histology, in addition to radiographic findings and clinical presentation, guides surgical management, the need for adjuvant therapies, and the optimal approach to long-term follow-up. Radioactive iodine (RAI) is used to reduce recurrence and improve survival for differentiated thyroid carcinomas (DTCs). Emerging systemic therapies provide options for patients with progressive metastatic MTC or radio-resistant DTC. Overall, the prognosis for the most common thyroid malignancy, papillary thyroid carcinoma (PTC), is excellent. The treatment of young adult thyroid cancer patients occurs optimally as part of a multidisciplinary coordination of care.