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The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.

Background: Thyroid cancer patients with radioiodine-refractory (RAI-R) disease, resulting from insufficient RAI delivery and/or RAI resistance, have increased mortality and limited treatment options. To date, studies have largely focused on tumor mutations associated with different stages of disease, which could provide prognostic value for RAI-R disease. It was hypothesized that germline variants contributing to intrinsic differences in iodine metabolism, tumor microenvironment, and/or immune surveillance are associated with RAI-R disease. Methods: Whole-genome genotyping data analysis was performed on 1145 Caucasian (CAU) patients, 244 of whom were RAI-R, and 55 African American (AA) patients, nine of whom were RAI-R. Germline-variant association studies were conducted using candidate genes involved in iodine metabolism or DNA-damage repair, as well as genome-wide association analysis. Initial data indicated several notable variants in a small number of patients (n = 7), who were later determined to be AA patients of >80% African ancestry (n = 37). This led to the study focusing on germline single nucleotide polymorphisms uniquely associated with RAI-R AA patients. Sanger sequencing was performed to validate risk alleles and identify the incidence of the common somatic mutations BRAF(V600E), NRAS(Q61R), and HRAS(Q61R) in AA patients whose primary tumor samples were available (28/55). Results: TG, BRCA1, and NSMCE2 haplotypes were identified as being uniquely associated with RAI-R AA patients of >80% African ancestry. All patients with the TG haplotype (n = 4) had a biochemical incomplete response to RAI therapy. Patients with the NSMCE2 haplotype (n = 4) were diagnosed at a young age (13, 17, 17, and 26 years old) with distant metastatic disease at initial diagnosis. The BRCA1 haplotype co-occurred in three out of four patients with the NSMCE2 haplotype. The incidence of BRAF(V600E) appears lower in papillary thyroid carcinomas from AA patients of >80% African ancestry (3/14; 21%) than in AA patients of

IMPORTANCE: Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent major advancements in treatment and OS has yet to be evaluated. OBJECTIVE: To evaluate rates of OS in patients with ATC over the last 2 decades. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study in a single tertiary care institution. Patients with histopathological confirmation of ATC from January 2000 to October 2019 were included and divided into 3 groups according to date of presentation: 2000-2013, 2014-2016, and 2017-2019. MAIN OUTCOMES AND MEASURES: Overall survival compared among different treatment eras and differing therapies, including targeted therapy, immunotherapy, and surgery. RESULTS: Of 479 patients (246 men [51%]; median age, 65.0 [range, 21.1-92.6] years) with ATC evaluated, 52 (11%) were stage IVA, 172 (36%) stage IVB, and 255 (53%) stage IVC at presentation. The median OS of the entire cohort was 0.79 years (9.5 months), ranging from 0.01 to 16.63. The OS at 1 and 2 years was 35% (95% CI, 29%-42%) and 18% (95% CI, 13%-23%) in the 2000-2013 group (n = 227), 47% (95% CI, 36%-56%) and 25% (95% CI, 17%-34%) in the 2014-2016 group (n = 100), and 59% (95% CI, 49%-67%) and 42% (95% CI, 30%-53%) in the 2017-2019 group (n = 152), respectively (P

Forty years ago, physicians caring for the J-kindred, a 100+ member family with multiple endocrine neoplasia type 2A (MEN2A), hypothesized that early thyroidectomy based on measurement of the biomarker calcitonin could cure patients at risk for development of medullary thyroid carcinoma (MTC). We re-evaluated 22 family members with proven RET proto-oncogene mutations (C634G) who underwent thyroidectomy and central lymphadenectomy between 1972 and 1994 based on stimulated calcitonin abnormalities. Current disease status was evaluated by serum calcitonin measurement and neck ultrasound in 18 of the 22 prospectively screened patients. The median age of the cohort at thyroidectomy was 16.5 years (range 9–24). The median duration of follow-up at the time of examination was 40 years (range 21–43) with a median current age of 52 years (range 34–65). Fifteen of the 18 patients had no detectable serum calcitonin (

BACKGROUND. No guidelines exist regarding physicians’ duty to inform former patients about novel genetic tests that may be medically beneficial. Research on the feasibility and efficacy of disseminating information and patient opinions on this topic is limited. METHODS. Adult patients treated at our institution from 1950 to 2010 for medullary thyroid cancer, pheochromocytoma, or paraganglioma were included if their history suggested being at-risk for a hereditary syndrome but genetic risk assessment would be incomplete by current standards. A questionnaire assessing behaviors and attitudes was mailed 6 weeks after an information letter describing new genetic tests, benefits, and risks was mailed. RESULTS. Ninety-seven of 312 (31.1%) eligible patients with an identified mailing address returned the questionnaire. After receiving the letter, 29.2% patients discussed genetic testing with their doctor, 39.3% considered pursuing genetic testing, and 8.5% underwent testing. Nearly all respondents (97%) indicated that physicians should inform patients about new developments that may improve their or their family’s health, and 71% thought patients shared this responsibility. Most patients understood the letter (84%) and were pleased it was sent (84%), although 11% found it upsetting. CONCLUSIONS. Patients believe it is important for physicians to inform them of potentially beneficial developments in genetic testing. However, physician-initiated letters to introduce new information appear inadequate alone in motivating patients to seek additional genetic counseling and testing. Further research is needed regarding optimal methods to notify former patients about new genetic tests and corresponding clinical and ethical implications.

Background The aim of this study was to investigate the genotype-phenotype relationship of pancreatic neuroendocrine tumors in patients with multiple endocrine neoplasia type 1 treated at our institution. Methods We conducted a retrospective chart review of all patients with multiple endocrine neoplasia type 1 treated at our center from January 1993 to December 2015. Presence of a pancreatic neuroendocrine tumor was determined based on imaging performed at any time from presentation to conclusion of follow-up. Results We reviewed 188 patients. The most common site of multiple endocrine neoplasia type 1 mutation was in exon 2 (34/188; 18%). Of 188 patients, 125 had a pancreatic neuroendocrine tumor (61%). Among all patients, 30 of 34 (88%) with an exon 2 mutation had a pancreatic neuroendocrine tumor compared with 95 of 154 (62%) with a mutation in exons 3–10 (P = .002). In the age group of 20 to 40 years, 8 of 9 patients with an exon 2 mutation had a pancreatic neuroendocrine tumor, compared with 24 of 52 patients (46%) with a mutation in exons 3–10 (P = .028). Patients with an exon 2 mutation had a greater frequency of pancreatic neuroendocrine tumor distant metastasis (53% vs 23%, P = .049). Conclusion Young patients with multiple endocrine neoplasia type 1 and an exon 2 mutation appear to have a 2-fold greater risk for developing a pancreatic neuroendocrine tumor, and patients with an exon 2 mutation may be at greater risk for developing distant metastasis. Consideration should be given to more intensive screening and more liberal application of primary operative intervention in this potentially high-risk group.

Context Interpretation of calcitonin measurement to predict the prognosis of medullary thyroid carcinoma (MTC) requires multiple measurements over an extended time period, making it an imperfect biomarker for evaluating prognosis or disease behavior. Single circulating cell-free DNA (cfDNA) values have been shown to be a valuable prognostic marker for several solid tumors. Objective We tested the hypothesis that cfDNA containing the RET M918T mutation could be detected in the blood of patients with advanced MTC whose tumor harbored an M918T mutation and would be able to predict overall survival more reliably than calcitonin. Design The level of cfDNA containing RET M918T mutation was measured in the plasma of patients with MTC via droplet digital polymerase chain reaction. Patients Patients had a confirmed sporadic MTC diagnosis, a serum calcitonin measurement >100 pg/mL, and tumor tissue biopsy results providing RET M918T mutation status. There were 75 patients included in this study, 50 of whom harbored an RET M918T mutation by tissue biopsy. Results RET M918T cfDNA was detected in 16 of 50 patients (32%) with a positive tissue biopsy. The detection of RET M918T cfDNA strongly correlated with worse overall survival and more accurately predicted a worse outcome than calcitonin doubling time. Conclusions Liquid biopsy is able to detect RET M918T mutations in patient plasma with high specificity but low sensitivity. In patients with established somatic RET M918T mutations, the allelic fraction of circulating tumor DNA is prognostic for overall survival and may play a role in monitoring response to treatment.

Background: Historical data suggests differentiated thyroid cancer (DTC) patients (pts) with brain metastases (mets) have overall survival (OS) of approximately 1 year; other reports refer median OS of 33months. Little is known about the mutation profile these pts. The TCGA indicates a median of 1 mutation in pts with PTC, most of which were low risk cases. Methods: We retrospectively studied clinical characteristics including number of lesions, therapeutic modalities, OS and mutational profile of TC pts with brain mets at a single cancer center between 2013-2018. Cases were identified by ICD-9 & -10 codes for TC and secondary neoplasm of brain but excluded if a separate malignancy accounted for brain mets. Somatic mutations were tested by targeted next-generation sequencing in the majority of cases. Results: Of 105 cases reviewed, 52 met entry criteria. Median age at diagnosis of brain mets was 62.5 years (4-85years); 31/52 (59.6%) were males. DTC accounted for the majority of the pts, 37/52 (71%) [papillary thyroid cancer 55.8%(PTC; 29/52); poorly differentiated thyroid cancer (PDTC; 5/52) 9.6%; follicular thyroid cancer 5.8% (3/52); Hurthle cell 0/52]; anaplastic thyroid cancer (ATC) 21.1% (11/52) & medullary thyroid cancer 7.7% (4/52). Symptoms were present in 50%, predominantly weakness 9/26 (34.6%), headaches 6/26 (23.1%), altered mental status 5/26 (19.2%), visual changes 5/26 (19.2%) and seizures 4/26 (15.4%). 47 pts received systemic therapy as follows: antiangiogenic drug 26/47 (55%); BRAF inhibitor alone or in combination with MEK inhibitor 22/47 (46.8%) and checkpoint inhibitors 16/47 (34%). Molecular testing was available in 50 cases. Known oncogenic driver mutations were noted in 86%(43/50); BRAF V600E mutated in 25/50 (50%), RAS 14/50 (28%; NRAS n=11, HRAS n=2, KRAS n=1), RET mutated in 4 cases. Of 25 pts tested for TERT promoter mutation 8 (32%) were positive. Mean number +/- SD of somatic mutations was 2.14 +/- 1.15 in PTC; 2.6 +/-1.62 in PDTC; and 5.45 +/- 4.6 in ATC. In terms of number of brain lesions, 38.5% had ≥3 metastatic foci. Treatment consisted of radiation [stereotactic radiosurgery 22/50 (44%), whole brain radiation 10/50 (20%)] and 13/50 (26%) surgical intervention. Median OS was 29.7 months (95% CI 12.5-NR) after brain mets diagnosis. 1-year survival by number of brain metastases was 76% for single focus (n=17), 66% for 2 (n=15) and 50% (n=20) for ≥3 (p=0.034). One year OS for surgically treated vs radiation was not statistically different. 1-year OS for DTC was 65% (95% CI 51%, 82%) vs 53% in ATC (95% CI 30%, 94%) p-value=0.996. The OS in symptomatic vs silent brain mets was 19.9 months vs 29.6 months (p value= 0.45). Conclusions: Mutation burden appears to be higher in TC pts with brain mets compared to TCGA. In TC pts with brain mets, survival decreases as number of lesions increases. The OS was slightly shorter in pts with symptomatic brain mets but not statistically significant.

Background The cyclin-dependent-kinase inhibitor/retinoblastoma pathway has been implicated in sporadic medullary thyroid carcinoma tumorigenesis. Somatic CDKN2C loss has been associated with decreased overall survival in medullary thyroid carcinoma patients. We evaluated CDKN2C loss in a prospective clinical environment using a novel Clinical Laboratory Improvement Amendments–certified assay to confirm its association with aggressive disease and to interrogate response to targeted therapy. Methods Patients with advanced sporadic medullary thyroid carcinoma underwent tumor genotyping for the purpose of management of targeted therapy and prognostication. Results Of patients with informative CDKN2C assay results, 30 (51.8%) were haploinsufficient/1N and 28 (48.3%) were 2N. Forty patients (69.0%) had a somatic RET mutation, and 36.9% had alterations of both genes. Thirty patients (51.7%) were treated with systemic therapy. Presence of genetic alterations in CDKN2C or RET did not predict treatment response. Patients with 1N CDKN2C loss had significantly shorter time-to-distant-metastasis than patients with normal copy number (P = .03). Conclusion This is the first evaluation in the clinical setting of CDKN2C haploinsufficiency in sporadic medullary thyroid carcinoma. Although a larger cohort and longer follow-up will be required, loss seems to be associated with more aggressive disease and may indicate patients that might receive benefit from treatment with a CDK inhibitor.

NHERF1/EBP50, an adaptor molecule that interacts with β-catenin, YAP, and PTEN, has been recently implicated in the progression of various human malignancies, including colorectal cancer. We report here that NHERF1 acts as a tumor suppressor in vivo for intestinal adenoma development. NHERF1 is highly expressed at the apical membrane of mucosa intestinal epithelial cells (IECs) and serosa mesothelial cells. NHERF1 -deficient mice show overall longer small intestine and colon that most likely could be attributed to a combination of defects, including altered apical brush border of absorbtive IECs and increased number of secretory IECs. NHERF1 deficiency in Apc Min/+ mice resulted in significantly shorter animal survival due to markedly increased tumor burden. This resulted from a moderate increase of the overall tumor density, more pronounced in females than males, and a massive increase in the number of large adenomas in both genders. The analysis of possible pathways controlling tumor size showed upregulation of Wnt-β-catenin pathway, higher expression of unphosphorylated YAP, and prominent nuclear expression of cyclin D1 in NHERF1-deficient tumors. Similar YAP changes, with relative decrease of phosphorylated YAP and increase of nuclear YAP expression, were observed as early as the adenoma stages in the progression of human colorectal cancer. This study discusses a complex role of NHERF1 for intestinal morphology and presents indisputable evidence for its in vivo tumor suppressor function upstream of Wnt-β-catenin and Hippo-YAP pathways.

Background Radiation-associated fusion oncogenes play a direct role in papillary thyroid cancer development and pathogenic fusions have recently been reported in medullary thyroid cancer. To date, no studies have evaluated oncogenic events in medullary thyroid cancer in a radiation-exposed population. Methods Somatic and germline alterations, including RET fusions, were evaluated in paired medullary thyroid cancer tumor and normal samples from the Chernobyl Tissue Bank, a heavily screened population affected by the Chernobyl disaster. Results Tissue was available for 49 individuals. The median age of diagnosis was 26 years (range 9 to 43 years); 16 were radiation-exposed at a median age of 6 (range 2 days to 17 years). A total of 21 patients harbored germline RET mutations (codons 634[13], 918[5], 790[1], 609[1], and 620[1]); 4 had family history. Sporadic medullary thyroid cancer was identified in 27 patients (RET[18], KRAS[1], RET+KRAS[1], TP53[1], wild type [6]), with 1 RET fusion (1/49;2%). The age at operation for patients with hereditary medullary thyroid cancer was not different than sporadic medullary thyroid cancer (23.5 vs 28 years, P = .063). In sporadic medullary thyroid cancer, radiation was not associated with a difference in age at operation, tumor size, or tumor stage (P > .05). Conclusion In a heavily screened cohort, genetic analysis revealed germline RET mutations in previously unrecognized probands and a remarkable number of sporadic medullary thyroid cancer cases with a young age at presentation.

Many advances have been made in the field of thyroid cancer for patients with locally advanced, unresectable and/or metastatic disease. There are now four anti-angiogenic multikinase inhibitors approved for medullary and differentiated thyroid cancer. However, as with other solid tumors, patients develop resistance to these targeted therapies or have contraindications to the approved therapies. Alternatives to the anti-angiogenic class of drugs are needed for these patients, thus, testing other drugs in thyroid cancer will be important in order to continue to advance the field. In May 2018, the FDA approved the combination of dabrafenib plus trametinib for BRAF V600E mutated anaplastic thyroid cancer, but eventually resistance ensues. Also, treatments for non-BRAF mutated patients are in great need. Gaining a better understanding of the mechanisms of resistance to targeted therapy will also be important in order to rationally modify treatment regimens. This chapter focuses on emerging treatments in clinical trials, translational studies that may one day lead to a better understanding of the mechanisms of resistance to targeted therapies and new strategies to identify patients suited for a particular genomic-driven therapy, as these will shape the future directions of thyroid cancer research.

Anaplastic thyroid cancer is a rare and aggressive thyroid cancer with an overall survival measured in months. Because of this poor prognosis and often advanced age at presentation, these patients have traditionally been treated palliatively and referred for hospice. However, recent progress using novel therapies has energized the field, and several promising clinical trials are now available for these patients. This review will highlight this progress and the potential treatments that could pave the way to improved outcomes and quality of life for patients with this disease.

Context Germline RET K666N mutation has been described as a pathogenic mutation with low disease penetrance for medullary thyroid cancer (MTC) without other features of multiple endocrine neoplasia type 2A. We describe a patient with homozygous RET K666N mutation with MTC and bilateral pheochromocytoma (PHEO). Case Description A 59-year-old woman received a diagnosis of MTC after biopsy of two thyroid nodules. Coincident biochemical and radiologic testing was suspicious for bilateral PHEO, confirmed after bilateral adrenalectomy. There was no evidence of primary hyperparathyroidism (PHPT). She had a total thyroidectomy with neck dissection revealing bilateral MTC with lymph node metastases. Germline RET testing identified homozygous K666N mutations. Genetic testing of family members showed that both adult children harbor a heterozygous K666N mutation. Her 32-year-old son had an elevated calcitonin level and underwent thyroidectomy, which identified MTC. Her 30-year-old daughter had a normal calcitonin level. Prophylactic thyroidectomy showed C-cell hyperplasia only. Three of seven other family members were tested and found to carry the mutation. All had normal calcitonin levels, and none had biochemical evidence of PHEO or PHPT. Given the absence of PHEO in reported RET K666N families, our proband underwent genetic testing for causes of hereditary paragangliomas or PHEO. No additional mutations were identified. Conclusions Here we report a case of a homozygous RET K666N mutation leading to coincident MTC and PHEO. Heterozygous presentations of RET K666N mutations have low penetrance for isolated MTC. We believe that the gene dosage associated with the homozygosity of this variant contributed to the occurrence of bilateral PHEO.

Mutation of the genes encoding the succinate dehydrogenase (SDH) subunits A, B, C, or D, or the SDHAF2 protein, cause the SDHx-hereditary paraganglioma syndromes. Hereditary susceptibility to metastatic sympathetic pheochromocytomas and paragangliomas is most commonly due to germline mutations in the SDHB gene. Individuals with SDHD mutations occasionally present with metastatic disease, while conversely malignant paragangliomas are rarely observed in SDHC carriers. A 43 year-old woman presented with an abdominal paraganglioma metastatic to the skeleton and multiple lymph nodes. The tumor produced excessive amounts of noradrenaline causing hypertension and symptoms of catecholamine excess. The patient underwent surgical resection of the primary tumor and lymph node metastases. Loss of SDHB protein expression in the primary tumor was demonstrated by immunohistochemistry. Germline sequencing and deletion testing revealed a large allelic deletion of exons 1-6 in SDHC, and no mutations or deletions were detected in SDHB or SDHD. The patient's mother died because of kidney cancer. Hereditary pheochromocytomas and paragangliomas may be associated with a deletion of the SDHC gene. These patients may present with malignant sympathetic paragangliomas.

Oncogenic RET tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. Although RET point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma (MTC), no fusions have been described to date.We evaluated the role of RET fusion as an oncogenic driver in MTC.We describe a patient who died from aggressive sporadic MTC10 months after diagnosis. Her tumor was evaluated by means of next-generation sequencing, including an intronic capture strategy.A reciprocal translocation involving RET intron 12 was identified. The fusion was validated using a targeted break apart fluorescence in situ hybridization probe, and RNA sequencing confirmed the existence of an in-frame fusion transcript joining MYH13 exon 35 with RET exon 12. Ectopic expression of fusion product in a murine Ba/F3 cell reporter model established strong oncogenicity. Three tyrosine kinase inhibitors currently used to treat MTC in clinical practice blocked tumorigenic cell growth.This finding represents the report of a novel RET fusion, the first of its kind described in MTC. The finding of this potential novel oncogenic mechanism has clear implications for sporadic MTC, which in the majority of cases has no driver mutation identified. The presence of a RET fusion also provides a plausible target for RET tyrosine kinase inhibitor therapies.

Context High-risk RET mutations (codon 634) are associated with earlier development of medullary thyroid carcinoma (MTC) and presumed increased aggressiveness compared with moderate-risk RET mutations. Objective To determine whether high-risk RET mutations are more aggressive. Design Retrospective cohort study using institutional multiple endocrine neoplasia type 2 registry. Setting Tertiary cancer care center. Patients Patients with MTC and moderate- or high-risk germline RET mutation. Intervention None (observational study). Main Outcome Measures Proxies for aggressiveness were overall survival (OS) and time to distant metastatic disease (DMD). Results A total of 127 moderate-risk and 135 high-risk patients were included (n = 262). Median age at diagnosis was 42.3 years (range, 6.4 to 86.4 years; mean, 41.6 years) for moderate-risk mutations and 23.0 years (range, 3.7 to 66.8 years; mean, 25.6 years) for high-risk mutations (P < 0.0001). Moderate-risk patients had more T3/T4 tumors at diagnosis (P = 0.03), but there was no significant difference for N or M stage and no significant difference in OS (P = 0.40). From multivariable analysis for OS, increasing age [hazard ratio (HR), 1.05/y; 95% confidence interval (CI), 1.03 to 1.08], T3/T4 tumor (HR, 2.73; 95% CI, 1.22 to 6.11), and M1 status at diagnosis (HR, 3.93; 95% CI, 1.61 to 9.59) were significantly associated with worse OS but high-risk mutation was not (P = 0.40). No significant difference was observed for development of DMD (P = 0.33). From multivariable analysis for DMD, only N1 status at diagnosis was significant (HR, 2.10; 95% CI, 1.03 to 4.27). Conclusions Patients with high- and moderate-risk RET mutations had similar OS and development of DMD after MTC diagnosis and therefore similarly aggressive clinical courses. High-risk connotes increased disease aggressiveness; thus, future guidelines should consider RET mutation classification by disease onset (early vs late) rather than by risk (high vs moderate).

Anaplastic thyroid cancer (ATC) is one of the most lethal forms of cancer with a high mortality rate. Current guidelines support surgery for resectable ATC followed by external beam radiation therapy (EBRT) with or without chemotherapy. Treatment for those who are unresectable is palliative. Our goal was to examine first-line therapies as well as the role of genomic profiling in an effort better understand how to approach ATC.This is a retrospective study of ATC patients who were seen at our institution from January 2013 to October 2015. Median overall survival (OS) and time to treatment failure (TTF) were calculated by the Kaplan-Meier method.Fifty-four patients were included. Median age at diagnosis was 63 years and 29/54 (54%) were women. The majority had stage IVC disease at diagnosis (50%), followed by IVB (32%), and IVA (18%). Approximately 93% had somatic gene testing. Initial treatment was surgery in 23 patients, EBRT with or without radiosensitizing chemotherapy in 29 patients, and systemic chemotherapy in 2 patients. Nineteen patients had all three treatment modalities. For the entire cohort, median OS was 11.9 months with 39% survival at 1 year and median TTF was 3.8 months. The majority of patients (74%) developed new distant metastasis or progression of existing metastatic disease. Patients who received trimodal therapy consisting of surgery, EBRT, and chemotherapy had a median OS of 22.1 months versus 6.5 months in those who received dual therapy with EBRT and chemotherapy (p = 0.0008). The TTF was the same in the two groups (7.0 and 6.5 months, respectively). Men were three times more likely to die from ATC than women (p = 0.0024). No differences in OS or TTF were noted based on tumor size (5 cm cutoff), age (60 years cutoff), or presence of any mutation. There was a trend toward shorter TTF in patients with somatic mutations in TP53.Patients with ATC amenable to aggressive tri-modal therapy demonstrate improved survival. The short TTF, due primarily to distant metastatic disease, highlights the potential opportunity for improved outcomes with earlier initiation of systemic therapy including adjuvant or neoadjuvant therapy.

Metastatic pheochromocytomas and paragangliomas (MPPs) present clinicians with three major challenges: scarcity, complexity of characterization, and heterogeneous behavior and prognosis. As with the treatment for all neuroendocrine tumors, the control of hormonal symptoms and tumor growth is the main therapeutic objective in MPP patients. A significant number of MPP patients still die from uncontrolled hormone secretion. In addition, the management of MPPs remains palliative. Steps forward include proper characterization of MPP patients at large cancer referral centers with multidisciplinary teams; improved strategies to stratify patients prognostically; and implementation of trials within national and international networks. Progress in the molecular characterization and staging of MPPs constitutes the basis for significant treatment breakthroughs.

Background: Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy. Methods: From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs. no MTC after thyroidectomy or no clinical evidence of MTC if thyroid intact). Data were used to estimate the cumulative prevalence of MTC and/or assess likelihood of MTC stratified by codon. After exclusion of cases with missing data or small representation, 503 patients with mutations in codons 533, 609, 611, 618, 620, 791, and 804 were analyzed. Results: 236 patients had MTC. Cumulative prevalence and median time to MTC varied by codon and within ATA risk levels (p

Primary hyperparathyroidism (PHPT) is uncommon in children. The surgical management of PHPT in children has evolved over the past two decades.A retrospective study of patients who underwent parathyroidectomy for PHPT diagnosed at age18 years and managed at a tertiary referral center for endocrine and familial disorders.Thirty-eight patients met eligibility criteria (1981-2012). Median age at PHPT diagnosis was 15 years. Two-thirds of patients were symptomatic (68%, n=26), most commonly from nephrolithiasis. Twenty-six (68%) patients underwent a standard cervical exploration while 32% underwent a focused unilateral parathyroidectomy. Multiple endocrine neoplasia type 1 (MEN1) was diagnosed preoperatively in 22/26 patients. Patients with a preoperative diagnosis of MEN1 were more likely to undergo a complete initial operation (≥ 3 gland parathyroidectomy with transcervical thymectomy, 13/22, 59% vs. 0/4, 0%; P=0.03) and less likely to have recurrent disease (10/22, 45% vs. 3/4, 75%; P0.001) during follow up than patients diagnosed postoperatively.Children with PHPT should raise suspicion for MEN1. Preoperative MEN1 evaluation helped guide the extent of initial parathyroidectomy and was associated with lower rates of recurrence in sporadic and familial PHPT in pediatric patients. Management should occur at a high volume center with experienced clinicians and genetic counseling services.

BackgroundMultiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.MethodsThe clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed.ResultsFour probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.ConclusionsFrom this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

Several guidelines for patients with multiple endocrine neoplasia 2A (MEN2A) take into account genotype and family history of medullary thyroid carcinoma (MTC) disease aggressiveness. We sought to determine if an association exists independent of genotype, which could provide important information for counseling MEN2A patients in management of their MTC. Pedigrees of patients with ≥5 family members with MEN2A were retrospectively reviewed. Analysis was performed among kindreds with the most frequently observed codon mutation (RET 634). Familial MTC disease aggressiveness was evaluated using: (1) mean age at diagnosis of MTC, (2) current mean age of carriers without MTC, (3) proportion of kindred with MTC with metastatic disease at diagnosis, (4) proportion of kindred with MTC with metastasis/death from MTC as worst outcome, and (5) proportion of kindred with disease progression. 170 affected patients from 12 different MEN2A kindreds met inclusion criteria. The number of affected family members available for study per kindred ranged from 8 to 43 individuals. A difference in mean age of MTC diagnosis was found in screened patients (p = 0.01); mean age of MTC-free patients did not differ (p = 0.93). No differences were noted among kindreds in disease stage at presentation, worst outcome, or progression; marked variation in these measures was noted within families. In conclusion, a difference in age of MTC diagnosis among different RET 634 kindreds was identified. In contrast, notable intra-familial variability in disease aggressiveness was observed. Based on these findings, we recommend counseling patients with codon 634 mutations that their MTC disease course cannot be predicted by that of their relatives.

Context: Individual patient prognostication for advanced thyroid cancer (TC) is challenging. Circulating tumor cells (CTCs) have been shown to be a valuable prognostic marker for other solid cancers. Objective: We hypothesized that CTCs are present in the blood of patients with advanced TC and their number can predict overall survival (OS). Setting: This is a prospective study at a tertiary cancer hospital. Patients, Interventions, and Main Outcome Measures: Initial studies were performed with TC cell lines to determine the feasibility of detection using the Veridex CellSearch. CTC enumeration was performed in blood samples from 18 patients with distantly metastatic medullary TC (metMTC), 14 with distantly metastatic differentiated TC (metDTC), and 10 controls with a history of TC but no evidence of disease. The prognostic value of CTC levels to predict OS in metMTC patients was assessed. Results: CellSearch detected cells from MTC and DTC but not anaplastic TC cell lines. Six metMTC patients but no metDTC or control patients had more than or equal to 5 CTCs detected by the CellSearch assay. Median survival in metMTC patients with more than or equal to 5 CTCs was 13 months vs 51.5 months for those with less than 5 CTCs (P = .0116). The hazard ratio for mortality of patients with more than or equal to 5 CTCs compared with those with less than 5 CTCs was 3.95 (1.20–13.0, P = .0245). Conclusions: The presence of more than or equal to 5 CTCs in patients with metMTC is associated with worse OS. Larger cohorts are required to validate the prognostic value of CTC enumeration.

Background: The cyclin-dependent-kinase inhibitors (CDKN)/retinoblastoma (RB1) pathway has been implicated as having a role in medullary thyroid carcinoma (MTC) tumorigenesis. CDKN2C loss has been associated with RET-mediated MTC in humans but with minimal phenotypic correlation provided. The objective of this study was to evaluate the association between tumor RET mutation status, CDKN2C loss, and aggressiveness of MTC in a cohort of patients with sporadic disease. Methods: Tumors from patients with sporadic MTC treated at a single institution were evaluated for somatic RET(M918T) mutation and CDKN2C copy number loss. These variables were compared to patient demographics, pathology detail, clinical course, and disease-specific and overall survival. Results: Sixty-two MTC cases with an initial surgery date ranging from 1983 to 2009 met the inclusion criteria, of whom 36 (58%) were male. The median age at initial surgery was 53 years (range 22–81 years). The median tumor size was 30 mm (range 6–145 mm) with 29 (57%) possessing extrathyroidal extension. Nodal and/or distant metastasis at presentation was found in 47/60 (78%) and 12/61 (20%) patients, respectively. Median follow-up time was 10.5 years (range 1.1–27.8 years) for the censored observations. The presence of CDKN2C loss was associated with worse M stage and overall AJCC stage. Median overall survival of patients with versus without CDKN2C loss was 4.14 [confidence interval (CI) 1.93–NA] versus 18.27 [CI 17.24–NA] years (p

Pheochromocytoma (PHEO) occurs in 50% of patients with multiple endocrine neoplasia type 2 (MEN2). It is unknown if the presence of PHEO is associated with more aggressive medullary thyroid cancer (MTC).To present our experience with MEN2 PHEO and evaluate whether PHEO impacts MTC overall survival in patients with RET codon 634 mutations.We performed a retrospective chart review of MEN2 patients at MD Anderson Cancer Center from 1960 through 2012.The study group comprised 85 patients (group 1) with MEN2-associated PHEO. Of these, 59 patients (subgroup 1) with RET codon 634 mutations were compared to 48 patients (group 2) with RET codon 634 mutations, but without MEN2-associated PHEO.Of 85 patients with MEN2 and PHEO, 70 had MEN2A and 15 had MEN2B. Median age at PHEO diagnosis was 32 years. The initial manifestation of MEN2 was MTC in 60% of patients, synchronous MTC and PHEO in 34%, and PHEO in 6% of patients. Of patients, 72% had bilateral PHEO, and most tumors were synchronous (82%). Subgroup analysis of MEN2 patients with and without PHEO, who were carriers of RET codon 634, the most common mutation with PHEO, showed no significant differences in the stage of MTC at initial diagnosis. The median follow-up time for patients with PHEO was 249 months and without PHEO was 67 months (P.01). Survival analyses among RET 634 carriers did not show shorter survival for patients with PHEO. The median survival time for patients with PHEO was 499 months and without PHEO was 444 months (P.05).PHEO in MEN2 patients are usually bilateral and unlikely to be metastatic. Subgroup analysis of patients with RET 634 mutations with and without PHEO showed that PHEO was not associated with a more advanced stage of MTC at diagnosis or a shorter survival.

Background Controversy exists regarding the role and extent of operation for patients with multiple endocrine neoplasia type 1 (MEN1) and hypergastrinemia. Methods An institutional MEN1 database was reviewed to identify patients with evidence of hypergastrinemia. The relationship of extent of resection to achievement of eugastrinemia was evaluated. Results Operation was performed in 20 patients with MEN1 and hypergastrinemia with a median follow-up of 71 months. Duodenal gastrinomas were identified in 85% of patients who underwent duodenal evaluation. Nodal metastases were identified in 80%. Patients who underwent anatomic regional lymph node dissection (RLND) had a median of 16 nodes removed, vs 1 in patients who did not undergo a formal regional lymphadenectomy. Eugastrinemia was achieved in 12 patients (60%), and 8 (40%) had persistent hypergastrinemia. Compared with patients with persistent hypergastrinemia, patients rendered eugastrinemic more often underwent duodenal evaluation (11/12 vs 2/8; P = .01) and RLND (11/12 vs 3/8; P = .03); there was no relationship between pancreatic resection and achievement of eugastrinemia (P = .32). Conclusion For patients with MEN1-associated hypergastrinemia selected for operative treatment, a strategy including duodenal evaluation and anatomic regional lymphadenectomy is associated with long-term eugastrinemia. In contrast, the extent of pancreatic resection should be dictated by the extent and distribution of pancreatic neuroendocrine neoplasms, rather than by the presence of hypergastrinemia.

Medullary thyroid carcinoma (MTC) and the multiple endocrine neoplasia (MEN) type 2 syndromes are rare but important endocrine diseases that are increasingly managed by pediatric providers. MTC is generally associated with a favorable prognosis when diagnosed during childhood, where it frequently occurs secondary to activating mutations in the RET proto-oncogene and arises from pre-existing C-cell hyperplasia. MEN2A accounts for 90-95% of childhood MTC cases and is most commonly due to mutations in codon 634 of RET. MEN2B is associated with the most aggressive clinical presentation of MTC and is almost always due to the Met918Thr mutation of RET. Surgery is the primary treatment and only chance of cure, although the advent of targeted therapies seems to be improving progression-free survival in advanced cases. Since the discovery of the role of RET in MEN2A, considerable advances in the management of this syndrome have occurred, and most of the children with MEN2A who have undergone early thyroidectomy will now lead full, productive lives. Strong genotype-phenotype correlations have facilitated the development of guidelines for interventions. Contemporary approaches for deciding the appropriate age at which surgery should take place incorporate data from ultrasonography and calcitonin measurements in addition to the results of genotyping. To optimize care and to facilitate ongoing research, children with MTC and the MEN2 syndromes are optimally treated at tertiary centers with multidisciplinary expertise.

6023Background: Anaplastic thyroid cancer (ATC) is a rare malignancy characterized by rapid progression and median overall survival (OS) of less than 6 months. With the goal of improving ATC outcom...

Objective To evaluate the expression of various phosphaturic factors in the tumor of a patient with tumorinduced osteomalacia (TIO) and to analyze serum levels of fibroblast growth factor (FGF)-23 in TIO and healthy subjects. Methods We measured serum FGF-23 levels in 2 patients with TIO and 6 healthy volunteers. Expression of FGF-23, matrix extracellular phosphoglycoprotein (MEPE), FGF-7, and secreted frizzled-related protein-4 (sFRP-4) was analyzed in a hemangiopericytoma from a patient with TIO, in a hemangiopericytoma from a patient without TIO, and in various control cell lines. Results Serum FGF-23 levels were substantially higher in patients with TIO in comparison with those in healthy control subjects and normalized with successful resection of the tumor. Tissue expression analysis showed preferential expression of FGF-23 and MEPE in TIO related hemangiopericytoma, whereas FGF-7 and sFRP-4 were widely expressed in all studied cell lines and tissues. Conclusion These results support the use of FGF-23 measurements for the diagnosis and follow-up of patients with TIO. In addition, the specific expression of FGF-23 and MEPE in the TIO-associated tumor suggests an important role of these two phosphatonins in the pathogenesis of TIO. Because of the limited number of patients in our report, further studies are needed to clarify the role of different phosphatonins in the development of the clinical features of TIO. (Endocr Pract. 2008;14:1108-1114)

Activating mutations in the RET protooncogene have been demonstrated in multiple endocrine neoplasia 2 and sporadic medullary thyroid carcinoma (MTC). However, the complete genetic etiology underlying MTC tumorigenesis remains unclear.Our objective was to define more precisely the chromosomal regions and uncover novel genes associated with MTC tumorigenesis.In this study, we used high resolution array-based comparative genomic hybridization to define tumor-associated copy number alterations (CNA) in 30 primary MTCs: 20 sporadic tumors (50% of which harbored RET mutation), and 10 hereditary.We identified 98 CNA, including 76 genomic allelic losses, two gains, and 20 copy number variations associated with MTC. Across sporadic and hereditary groups, there was a similar and overlapping pattern of predominant allelic loss. There were 29 regions containing at least 30% CNA in the 30 tumor samples. The most frequent allelic loss occurred in four loci, 7q36.1, 12p13.31, 13q12.11, and 19p13.3-11. No regions were found to be uniquely altered in the hereditary tumors. There were 21 CNA specific to sporadic MTC, with loss of 11q23.3 uniquely altered in RET negative tumors. Pathway analysis found cellular growth and proliferation as the most significant overall target, and cell death as the most significant pathway targeted in sporadic MTC.Our findings underscore the importance of candidate tumor suppressor genes together with RET alterations in MTCs. Despite of RET status, all MTC might share similar oncogenetic mechanisms. Dysfunction of cell proliferation and cell death may both be involved in MTC tumorigenesis.

Adrenocortical carcinoma is a rare malignancy with poor prognosis and limited response to chemotherapy. Hepatocyte growth factor (HGF) and its receptor cMET augment cancer growth and resistance to chemotherapy, but their role in adrenocortical carcinoma has not been examined. In this study, we investigated the association between HGF/cMET expression and cancer hallmarks of adrenocortical carcinoma. Transcriptomic and immunohistochemical analyses indicated that increased HGF/cMET expression in human adrenocortical carcinoma samples was positively associated with cancer-related biologic processes, including proliferation and angiogenesis, and negatively correlated with apoptosis. Accordingly, treatment of adrenocortical carcinoma cells with exogenous HGF resulted in increased cell proliferation in vitro and in vivo while short hairpin RNA–mediated knockdown or pharmacologic inhibition of cMET suppressed cell proliferation and tumor growth. Moreover, exposure of cells to mitotane, cisplatin, or radiation rapidly induced pro-cMET expression and was associated with an enrichment of genes (e.g., CYP450 family) related to therapy resistance, further implicating cMET in the anticancer drug response. Together, these data suggest an important role for HGF/cMET signaling in adrenocortical carcinoma growth and resistance to commonly used treatments. Targeting cMET, alone or in combination with other drugs, could provide a breakthrough in the management of this aggressive cancer. Cancer Res; 75(19); 4131–42. ©2015 AACR.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor deriving from the thyroid parafollicular cell. Thyroidectomy continues to serve as the primary initial treatment for this cancer. Because standard cytotoxic chemotherapy has proven ineffective, reoperation and external beam radiation therapy had been the only tools to treat recurrences or distant disease. The discovery that aberrant activation of RET, a receptor tyrosine kinase, is a primary driver of MTC tumorigenesis led to clinical trials using RET-targeting tyrosine kinase inhibitors. The successes of those trials led to the approval of vandetanib and cabozantinib for treating patients with progressive or symptomatic MTC. The availability of these drugs, along with additional targeted therapies in development, requires a thoughtful reconsideration of the approach to treating patients with unresectable locally advanced and/or metastatic progressive MTC.

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.The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure.This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013.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).Progression-free survival, best response, and median OS were measured.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).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.

The calcium-sensing receptor (CaR) is a G-protein-coupled receptor that is widely expressed, has tissue-specific functions, and regulates cell growth. Activating mutations of this receptor cause autosomal dominant hypocalcemia, a syndrome characterized by hypocalcemia and hypercalciuria. The identification of a family with an activating mutation of the CaR (Thr151Met) in which hypocalcemia cosegregates with several unusual neoplasms led us to examine the transforming effects of this mutant receptor. Transfection of NIH/3T3 cells with the mutant but not the normal receptor supported colony formation in soft agar at subphysiologic calcium concentrations. The mutant CaR causes a calcium-dependent activation of the extracellular signal-regulated protein kinase (ERK) 1/2 and Jun-N-terminal kinase/stress-activated (JNK/ SAPK) pathways, but not P38 MAP kinase. These findings contribute to a growing body of information suggesting that this receptor plays a role in the regulation of cellular proliferation, and that aberrant activation of the mutant receptor in this family may play a role in the unusual neoplastic manifestations.

Mutations in genes encoding the ATP-regulated potassium (K(ATP)) channels of the pancreatic beta-cell (SUR1 and Kir6.2) are the major known cause of persistent hyperinsulinemic hypoglycemia of infancy (PHHI). We collected all cases of PHHI diagnosed in Finland between 1983 and 1997 (n = 24). The overall incidence was 1:40,400, but in one area of Central Finland it was as high as 1:3,200. Haplotype analysis using polymorphic markers spanning the SUR1/Kir6.2 gene cluster confirmed linkage to the 11p region. Sequence analysis revealed a novel point mutation in exon 4 of SUR1, predicting a valine to aspartic acid change at amino acid 187 (V187D). Of the total cases, 15 affected individuals harbored this mutation in heterozygous or homozygous form, and all of these had severe hyperinsulinemia that responded poorly to medical treatment and required subtotal pancreatectomy. No K(ATP) channel activity was observed in beta-cells isolated from a homozygous patient or after coexpression of recombinant Kir6.2 and SUR1 carrying the V187D mutation. Thus, the mutation produces a nonfunctional channel and, thereby, continuous insulin secretion. This unique SUR1 mutation explains the majority of PHHI cases in Finland and is strongly associated with a severe form of the disease. These findings provide diagnostic and prognostic utility for suspected PHHI patients.

Medullary thyroid carcinoma (MTC) is a unique disease in solid tumor oncology due to its ability to secrete calcitonin (iCT), a highly sensitive and specific serum marker of persistent or recurrent disease even at a microscopic level. The relatively long duration of survival experienced by most patients with MTC combined with the visible nature of surgical complications, when they occur, has caused most surgeons to take a conservative approach to the operative management and follow-up of patients with MTC. In contrast, the patient, family physician, and endocrinologist watch the iCT slowly rise, indicative of persistent and usually progressive invasive cancer. Amidst this clinical dilemma, we developed a standardized diagnostic and operative strategy to maximize local-regional tumor control and facilitate patient management.

Objective. —Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could help in clinical decision making. Design. —Correlative survey study of 477 MEN 2 families. Setting. —Eighteen tertiary referral centers worldwide. Patients. —A total of 477 independent MEN 2 families. Main Outcome Measures. —Association between the position and type of germline mutation in the RET proto-oncogene and the presence or absence of MTC, pheo, HPT, and/or other features in a family. Results. —There is a statistically significant association between the presence of any mutation at a specific position (codon 634) and the presence of pheo and HPT. The presence of a specific mutation, CGC at codon 634, has yet to be associated with FMTC. Conversely, mutations at codons 768 and 804 are thus far seen only with FMTC, while codon 918 mutation is MEN 2B-specific. Rare families with both MEN 2 and Hirschsprung disease were found to have MEN 2-specific codon mutations. Patients with Hirschsprung disease presenting with such mutations should be monitored for the possible development of MEN 2 tumors. Conclusions. —This consortium analysis suggests that genotype-phenotype correlations do exist and, if made reliably absolute, could prove useful in the future in clinical management with respect to screening, surveillance, and prophylaxis, as well as provide insight into the genetic effects of particular mutations.

Multiple endocrine neoplasia, type 2B (MEN 2B), is a phenotypic variant of a group of autosomal-dominant neurocristopathies. MEN 2B is associated with medullary thyroid carcinoma and pheochromocytoma with oral, ocular, and alimentary submucosal ganglioneuromas and Marfanoid body features. Approximately 50% of cases are thought to be spontaneous mutations. The RET protooncogene (RET) is a 21-exon gene encoding a tyrosine kinase receptor. A codon 918 germ line mutation, which converts a highly conserved methionine to a threonine in the intracellular tyrosine kinase portion of this receptor of RET, has been identified in 95% of patients with MEN 2B. This mutation is easily detected by a direct deoxyribonucleic acid sequencing or restriction enzyme (Fok 1) analysis of amplified polymerase chain reaction products. The RET gene is normally expressed in the oral and gastrointestinal submucosal neural ganglia, and the codon 918 mutation is thought to cause neuromas by virtue of its transforming activity in these ganglia. Identifying clinical features of MEN 2B in an 11-year-old boy by an oral pathologist led to confirmation by mutational analysis. Before genetic testing was available, the patient, and at a later date his mother, underwent thyroidectomies based solely on biochemical testing. Results indicated the patient had the codon 918 mutation, whereas his phenotypically normal mother, father, and older brother had normal RET analyses. Studies in families have demonstrated that the mutant allele is derived from the father with possible acquisition during spermatogenesis. We believe the mother of our affected patient to be normal; the absence of phenotypic features of MEN 2B and a normal genotype suggest her calcitonin abnormalities and minimal evidence for C-cell hyperplasia were inconsequential. Molecular analysis for RET abnormalities will likely supplant biochemical methods of diagnosis in patients with MEN 2B.

Application of RET proto-oncogene mutation analysis to the clinical management of MEN 2 and FMTC has simplified and enhanced the power of earlier used screening and treatment efforts for hereditary MTC. The approaches outlined herein are cost-effective, have improved diagnostic accuracy, and hold the promise of improved cure rates for this neoplasm. Further studies to elucidate the mechanism by which these activating mutations cause transformation may lead to other strategies for prevention or treatment of this neoplasm.

The identification of RET proto-oncogene mutations in patients with MEN2 2 years ago was a watershed event in the management of this genetic cancer syndrome. The identification of a finite number of mutations that together causes more than 95% of hereditary and 15-25% of sporadic MTC has made it possible to develop simple and definitive tests to screen individuals at risk for this tumour syndrome. The impact of this technology is enormous. It is now possible to reassure 50% of family members at risk that they, and their children, do not have to worry about developing MTC. In the other 50% who are gene carriers, it is now possible to approach clinical management with greater certainty and plot strategies that are likely to result in a greater percentage of curative therapy. It seems likely that this technology will also have an impact on the management of sporadic MTC, although it is still too early to define a specific role for mutational analysis in these patients, except to exclude hereditary disease. The identification of specific mutations causative for MTC makes it possible to conceive future strategies for the treatment or prevention of MTC and to further extend the impact of these exciting findings.

Less than a decade after the identification of activating mutations of the rearranged during transfection (RET) proto-oncogene in multiple endocrine neoplasia type 2 (MEN-2), a clinical syndrome ch...

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.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.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.

Pheochromocytomas and sympathetic paragangliomas are rare neuroendocrine tumors for which no precise histological or molecular markers have been identified to differentiate benign from malignant tumors.The aim was to determine whether primary tumor location and size are associated with malignancy and decreased survival.We performed a retrospective chart review of patients with either pheochromocytoma or sympathetic paraganglioma.The study group comprised 371 patients.Overall survival and disease-specific survival were analyzed according to tumor size and location.Sixty percent of patients with sympathetic paragangliomas and 25% of patients with pheochromocytomas had metastatic disease. Metastasis was more commonly associated with primary tumors located in the mediastinum (69%) and the infradiaphragmatic paraaortic area, including the organ of Zuckerkandl (66%). The primary tumor was larger in patients with metastases than in patients without metastatic disease (P0.0001). Patients with sympathetic paragangliomas had a shorter overall survival than patients with pheochromocytomas (P0.0001); increased tumor size was associated with shorter overall survival (P0.001). Patients with sympathetic paragangliomas were twice as likely to die of disease than patients with pheochromocytomas (hazard ratio = 1.93; 95% confidence interval = 1.20-3.12; P = 0.007). As per multivariate analysis, the location of the primary tumor was a stronger predictor of metastases than was the size of the primary tumor.The size and location of the primary tumor were significant clinical risk factors for metastasis and decreased overall survival duration. These findings delineate the follow-up and treatment for these tumors.

Sympathetic paragangliomas are autonomic nervous system tumors associated with dysregulation of intracellular oxygen metabolism. Exposure to high altitudes is reported to activate the production of catecholamines in the sympathoadrenal system. We describe an individual with a paraganglioma complicated by a catecholamine crisis that occurred on the summit of Mount Kilimanjaro.

Medullary thyroid carcinoma (MTC) is a cancer of the parafollicular C cells commonly caused by an inherited or acquired RET proto-oncogene mutation. Therapeutic resistance and recurrence of the disease imply the presence of cancer stem cells in MTC.In this study, we sought to identify and characterize cancer stem cell-like cells in MTC.The characterization of stem cell properties was performed using immunostaining, flow cytometry, sphere formation assay, rederivation assay, Western blotting, and quantitative RT-PCR of defined markers of neural stem and progenitor cells. The role of ret proto-oncogene activation was assessed through RNA interference knockdown.CD133 positivity was identified by immunostaining patient MTC. Flow cytometry confirmed a subpopulation of CD133(+) cells in two MTC cell lines. The CD133(+) cells could be expanded by sphere formation assay, passaged multiple times, and expressed neural progenitor markers beta-tubulin 3 and glial fibrillary acidic protein. The MZ-CRC-1 cell line, which harbors a M918T RET mutation, had greater CD133(+) cell numbers and sphere-forming ability than the TT cell line, which harbors the less active C634W mutation. Sphere formation was more dependent on ret proto-oncogene activity than epidermal growth factor or fibroblast growth factor.Our data support the existence of cancer stem-like cells in MTC, which exhibit the features of self-renewal and of multiple lineage differentiation that is dependent on ret proto-oncogene receptor activity. These findings may provide new insights to develop more promising therapy for MTC.

Anaplastic thyroid carcinoma (ATC) can occur in the setting of differentiated thyroid carcinoma (DTC), which suggests a continuum in malignant progression from DTC to ATC. The Ras/Raf-MAPK and the phosphatidylinositol 3-kinase/Akt signaling pathways play critical roles in DTC tumorigenesis, but their roles in the pathogenesis of ATC are poorly defined.Our objective was to explore the potential contributions of these two pathways in ATC pathogenesis.The mutational status of BRAF, PIK3CA, PTEN, and RAS genes was analyzed in genomic DNA from microdissected tumor specimens of 36 cases of ATC, and in 16 samples of paired-matched lymph node metastases. PIK3CA copy number gain was assessed by real-time quantitative PCR. We performed immunohistochemistry for phospho-ERK and phospho-AKT in 26 cases of ATC.DTC was present in half of the cases. BRAF V600E mutation was identified in nine of 36 (25%) ATCs; seven cases had identical mutations in both the ATC and DTC components. PIK3CA kinase domain mutations were found in five (14%) ATCs, one of which had mutations in both differentiated and anaplastic areas. RAS and PTEN mutations were each found in two (6%) ATCs. PIK3CA gain copy number was found notably increased in 14 (39%) ATCs.BRAF mutations appear to play a role in the tumorigenesis of a subset of ATCs, and the majority of lymph node metastases. PIK3CA alterations occur preferentially in the later stages of ATC and were the most relevant events during thyroid cancer progression. The activation of both pathways suggests an important role in ATC dedifferentiation.