BRAF K601E Mutation in Oncocytic Carcinoma of the Thyroid: A Case Report and Literature Review.

BACKGROUND: Thyroid carcinoma (TC) is the most common endocrine cancer, with papillary thyroid carcinoma (PTC) being the most common subtype. BRAF and RAS oncogene were characterized as the most frequently altered genes in PTC, with a strong association between genotype and histotype. The most common mutation in BRAF gene is V600E and is prevalent in classic and aggressive variants of PTC, while BRAF K601E mutation is the most common among the other rare BRAF mutations. BRAF K601E mutated thyroid carcinomas are usually characterized by low aggressiveness, except for anecdotal cases of poorly differentiated TC. CASE PRESENTATION: We described a case of oncocytic carcinoma of the thyroid (OCA) with an aggressive clinical course, including widespread metastasis and resistance to radioiodine treatment. Molecular analysis revealed the exclusive presence of the BRAF K601E mutation in both primary tumor and metastatic lesions. Accordingly, a revision of the literature about aggressive TC cases carrying BRAF K601E mutation was performed. CONCLUSION: Although rare, this case emphasizes the relevance of considering BRAF K601E mutation in advanced non-PTC thyroid carcinomas, since it can be considered an actionable mutation for target therapies.

Chromosomal alterations in sporadic medullary thyroid carcinoma and correlation with outcome.

Somatic copy number alterations (SCNA) involving either a whole chromosome or just one of the arms, or even smaller parts, have been described in about 88% of human tumors. This study investigated the SCNA profile in 40 well-characterized sporadic medullary thyroid carcinomas by comparative genomic hybridization array. We found that 26/40 (65%) cases had at least one SCNA. The prevalence of SCNA, and in particular of chromosome 3 and 10, was significantly higher in cases with a RET somatic mutation. Similarly, SCNA of chromosomes 3, 9, 10 and 16 were more frequent in cases with a worse outcome and an advanced disease. By the pathway enrichment analysis, we found a mutually exclusive distribution of biological pathways in metastatic, biochemically persistent and cured patients. In particular, we found gain of regions involved in the intracellular signaling and loss of regions involved in DNA repair and TP53 pathways in the group of metastatic patients. Gain of regions involved in the cell cycle and senescence were observed in patients with biochemical disease. Finally, gain of regions associated with the immune system and loss of regions involved in the apoptosis pathway were observed in cured patients suggesting a role of specific SCNA and corresponding altered pathways in the outcome of sporadic MTC.

NF1 Gene Inactivation Acts as Tumor Driver in RET/RAS Negative Medullary Thyroid Carcinomas.

OBJECTIVE: 20% of sporadic MTC has no RET/RAS somatic alterations or other known gene alterations. Aim of this study was to investigate RET/RAS negative MTC for the presence of NF1 alterations. METHODS: we studied 18 sporadic RET/RAS negative MTC cases: Next generation sequencing of tumoral and blood DNA was performed using a custom panel including the entire coding region of the NF1 gene. The effect of NF1 alterations on the transcripts were characterized by RT-PCR and the loss of heterozygosity of the other NF1 allele was investigated with Multiplex Ligation-dependent Probe Amplification. RESULTS: Two cases showed bi-allelic inactivation of NF1 with a prevalence of about 11% of RET/RAS negative cases. In a patient affected by neurofibromatosis there was a somatic intronic point mutation determining the transcript alteration in one allele and a germline loss of heterozygosity (LOH) in the other. In the other case described both the point mutation and the LOH were somatic events; this latter finding shows, for the first time, a driver role of NF1 inactivation in MTC independent of RET/RAS alterations and the presence of neurofibromatosis. CONCLUSIONS: About 11% of our series of sporadic RET/RAS negative MTC harbor biallelic inactivation of NF1 suppressor gene also regardless neurofibromatosis status. According to our results, NF1 alterations should be searched in all RET/RAS negative MTC as possible driver. Moreover, this finding reduces the number of negative sporadic MTCs and may have important clinical implications in the management of these tumors.

Clinical Evolution of Sporadic Medullary Thyroid Carcinoma With Biochemical Incomplete Response After Initial Treatment.

CONTEXT: The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined. OBJECTIVE: This work aimed to evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetic features. METHODS: We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at the endocrine unit of the University Hospital of Pisa. RESULTS: After a median of 5 months from surgery, 145 of 599 (24.2%) patients were classified as BiR. Structural disease was detected in 64 of 145 (44.1%), after a median time of 3.3 years. In 73.6%, structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation. CONCLUSION: In sporadic MTC patients with BiR, the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, stricter follow-up should be reserved for MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should be considered for all BiR patients since 50% of them develop structural disease within 10 years.

Somatic RET Indels in Sporadic Medullary Thyroid Cancer: Prevalence and Response to Selpercatinib.

CONTEXT: Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET-specific inhibitors in patients harboring RET indels has been provided. OBJECTIVE: We present an update on the prevalence of RET indels in medullary thyroid cancer (MTC) and describe the efficacy of selpercatinib in patients with advanced MTC with RET indels. METHODS: The MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by MutationTaster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel were treated with selpercatinib. RESULTS: Among 178 RET-positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by MutationTaster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment. CONCLUSION: These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indel-positive patients showed a partial response to the treatment with a highly selective RET inhibitor; thus, these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended.

Pre- and Post-operative Circulating Tumoral DNA in Patients With Medullary Thyroid Carcinoma.

CONTEXT: Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors. OBJECTIVE: The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC). METHODS: We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcinoembryonic antigen (CEA), and other clinical/pathological features. RESULTS: Twenty-six of 29 (89.7%) sMTCs were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four of 26 (15.4%) cases showed positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P = 0.0468). Patients with positive pre-operative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P = 0.0434) and a higher frequency of persistent disease (P = 0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTCs and no one was positive for pre-operative ctDNA. Higher values of both Ct (P = 0.0307) and CEA (P = 0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA had a persistent disease (P = 0.0005) showing a higher post-operative serum Ct when compared with cases with negative ctDNA (P = 0.0092). CONCLUSIONS: Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results.

Active Surveillance in RET Gene Carriers Belonging to Families with Multiple Endocrine Neoplasia.

Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT); surgery preference of subjects (or parents, if subject less than 18 years old); other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.

Higher RET Gene Expression Levels Do Not Represent anAlternative RET Activation Mechanism in Medullary Thyroid Carcinoma.

This study was designed to investigate whether RET (rearranged during transfection) mRNA over-expression could be considered an alternative driver event for the development of medullary thyroid carcinoma (MTC), and if different RET isoforms could play a role in MTC tumorigenesis. Eighty-three MTC patients, whose mutational profile was previously identified by next-generation sequencing (NGS) IONS5, were included in this study. Expression analysis was performed by the quantitative reverse transcription-polymerase chain reaction technique. RET expression levels were found to be significantly higher in cases with RET somatic mutations than in cases that were negative for RET somatic mutations (p = 0.003) as well as in cases with a somatic mutation, either in RET or RAS than in cases negative for both these mutations (p = 0.01). All cases were positive for the RET51 isoform expression while only 72/83 (86.7%) were positive for RET9 isoform expression. A statistically significant higher expression of the RET51 isoform was found in cases positive for RET somatic mutation than in cases either positive for RAS mutation (p = 0.0006) or negative for both mutations (p = 0.001). According to our data, RET gene over-expression does not play a role in MTC tumorigenesis, neither as an entire gene or as an isoform. At variance, the RET gene, and in particular the RET51 isoform, is expressed higher in RET mutated cases. On the basis of these results we can hypothesize that the overexpression of RET, and in particular of RET51, could potentiate the transforming activity of mutated RET, making these cases more aggressive.

Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer.

CONTEXT: Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer. OBJECTIVE: This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC). METHODS: FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations. RESULTS: E-FVPTC was more frequent than E-CVPTC (P < .001). No differences were found between En-FVPTC and En-CVPTC or between Ei-FVPTC and Ei-CVPTC. After 18 years of follow-up, a greater number of not-cured cases were observed in Ei-CVPTC with respect to Ei-FVPTC, but not in En-CVPTC to En-FVPTC. Multivariate clustering analysis showed that En-FVPTC, En-CVPTC, and Ei-FVPTC have similar features but different from I-FVPTC and I-CVPTC and, to a lesser extent, from Ei-CVPTC. A total of 177 of 614 (28.8%) cases were BRAFV600E mutated, and 10 of 614 (1.6%) carried BRAF-rare alterations. A significantly higher rate of En-CVPTC (22/49, 44.9%) than En-FVPTC (15/195, 7.7%) (P < .0001) were BRAFV600E mutated. CONCLUSION: En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged.

RET mutated C-cells proliferate more rapidly than non-mutated neoplastic cells.

A statistically significant higher prevalence of the RET p.Met918Thr somatic mutation, identified by direct sequencing, was previously reported in MTC > 2 cm than in smaller tumors. Aim of this study was to correlate the full RET and RAS mutation profile, identified by a Next Generation Sequencing approach, with the growth rate, proliferation and tumor size of MTC. Data of 149 sporadic MTC patients were correlated with RET mutations and Ki67 positivity. Eighty-one cases had a somatic RET mutation, 40 had a RAS mutation and 28 were negative. A statistically significant higher prevalence of RET mutations was found in MTC > 2 cm. A higher prevalence of RET more aggressive mutations, higher allelic frequencies and, higher percentage of Ki67 positive cells were found in larger tumors which had also a worse outcome. Our study highlights the predominant role of RET somatic mutations in MTC tumorigenesis. We demonstrate that RET mutation prevalence and allelic frequency (AF) are significantly higher in larger tumors. Based on these results, we can conclude that RET mutated C-cells's growth and proliferation are more rapid than those of non-mutated cells and give origin to bigger and more aggressive MTC.

A New MEN2 Syndrome with Clinical Features of Both MEN2A and MEN2B Associated with a New RET Germline Deletion.

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by RET proto-oncogene mutation. Two different clinical variants of MEN2 are known (MEN2A and MEN2B): medullary thyroid carcinoma (MTC) almost always present and associated with pheochromocytoma (Pheo), and primary hyperparathyroidism (HPTH) in MEN2A and with Pheo and other nonendocrine diseases in MEN2B. Case Report. A 7-year-old girl, previously treated for a pelvic plexiform neurofibroma, arrived at our observation with a peculiar MEN2B syndrome and with HPTH. The neck ultrasound showed bilateral thyroid nodules, local lymph node lesions, and a suspicious left hyperplastic parathyroid. The CT scan showed a megacolon and described the persistence of the pelvic tumor. A new RET germline deletion in exon 11 (c.1892_1899delCGAGCT; p.Glu632_Leu633del) was found. She underwent total thyroidectomy, central compartment and latero-cervical lymph node dissection, and neck exploration for primary HPTH. The histology confirmed bilateral MTC, multiple lymph node metastases, a hyperplastic parathyroid, and a parathyroid adenoma. CONCLUSIONS: This is the first case of a complex syndrome characterized by peculiar features of MEN2B, without Pheo but with a pelvic plexiform neurofibroma and with HPTH, which is typical of MEN2A. A "de novo" new germline RET deletion located in exon 11 was found.

RET Copy Number Alteration in Medullary Thyroid Cancer Is a Rare Event Correlated with RET Somatic Mutations and High Allelic Frequency.

Copy number variations (CNV) of the RET gene have been described in 30% of Medullary Thyroid Cancer (MTC), but no information is available about their role in this tumor. This study was designed to clarify RET gene CNV prevalence and their potential role in MTC development. RET gene CNV were analyzed in 158 sporadic MTC cases using the ION Reporter Software (i.e., in silico analysis) while the multiplex ligation-dependent probe amplification assay (i.e., in vitro analysis) technique was performed in 78 MTC cases. We identified three categories of RET ploidy: 137 in 158 (86.7%) cases were diploid and 21 in 158 (13.3%) were aneuploid. Among the aneuploid cases, five out of 21 (23.8%) showed an allelic deletion while 16 out of 21 (76.2%) had an allelic amplification. The prevalence of amplified or deleted RET gene cases (aneuploid) was higher in RET positive tumors. Aneuploid cases also showed a higher allelic frequency of the RET driver mutation. The prevalence of patients with metastatic disease was higher in the group of aneuploid cases while the higher prevalence of disease-free patients was observed in diploid tumors. A statistically significant difference was found when comparing the ploidy status and mortality. RET gene CNVs are rare events in sporadic MTC and are associated with RET somatic mutation, suggesting that they could not be a driver mechanism of tumoral transformation per se. Finally, we found a positive correlation between RET gene CNV and a worse clinical outcome.

Medullary thyroid cancer treated with vandetanib: predictors of a longer and durable response.

Vandetanib is an important treatment option for advanced metastatic medullary thyroid cancer. The aims of this study were to evaluate the predictors of both a longer response to vandetanib and the outcome. Medical records of 79 medullary thyroid cancer patients treated with vandetanib at our center were analysed. Twenty-five patients were treated for <12 months, 54 were treated for ≥12 months and 24 of these latter were treated for ≥48 months (short-, long- and very long-term). The median progression free survival of the long and very long-term treated patients was significantly longer than in the ZETA trial. When comparing the groups of short - and long-term treated patients the only significant difference was that these latter were less frequently previously treated with a tyrosine kinase inhibitor. However, the long-term treated patients had a younger age, both at diagnosis and enrolment, which was statistically significant in the very long-term treated patients. In the long-term treated group, younger age, enrolment for symptoms and development of adverse events were significantly correlated with a better outcome. The enrolment for symptoms remained the only statistically significant predictor of a good outcome in the very long-term treated patients. In conclusion, early treatment with vandetanib, when patients are younger, with a good ECOG performance status and symptomatic disease, not necessarily progressing for RECIST, seem to be the best predictors of a longer and durable response. Further studies are needed to confirm these results

Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing.

Sporadic Medullary Thyroid Carcinoma (sMTC) is a rare but aggressive thyroid tumor. RET and RAS genes are present in about 50%-80% of cases, but most of the remaining cases are still orphan of a genetic driver. We studied the largest series of sMTC by deep sequencing to define the mutational landscape. With this methodology we greatly reduced the number of RET- or RAS-negative cases and we confirmed the central role of RET and RAS mutations. Moreover, we highlighted the bad prognostic role of RET mutations in sMTC and consolidated the favorable prognostic role of RAS mutations. For the first time, we showed that the variant allele frequency represents an additional prognostic marker inside the group of RET-mutated sMTC.

Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations.

BACKGROUND: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. METHODS: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. RESULTS: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were "de novo" and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. CONCLUSIONS: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype-phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.

Differential expression of RET isoforms in normal thyroid tissues, papillary and medullary thyroid carcinomas.

POURPOSES: We investigated the expression of RET9 and RET51 isoforms in medullary (MTC), papillary (PTC) thyroid carcinoma, normal thyroid tissues, and pheochromocytoma (PHEO) to verify if these isoforms are present also in follicular thyroid cell-derived tissues, and if there is a differential expression of RET9 and RET51 in MTC. METHODS: Nineteen patients with MTC, 18 patients with PTC, 18 samples of contralateral normal thyroid tissues, and 5 cases of PHEO were included in this study. RET isoform expression was studied by real-time RT-PCR. RESULTS: All MTCs and PHEOs were positive for RET9 and RET51. Fourteen/eighteen (77.7%) PTC cases were positive for RET9 and/or RET51, and four were positive for only one of the genes. In normal thyroid tissues, 3/18 (16.7%) cases were negative for both isoforms, 4/18 (22.2%) were positive for both, and 11/18 (61.1%) were positive for only one. RET isoforms were expressed at different levels in MTC, PHEO, PTC, and normal thyroid tissues: RET9 expression was higher in PHEO than in MTC, PTC, and normal thyroid tissues. RET9 expression was also higher in MTC than in PTC and normal thyroid tissues. No difference was observed between PTC and normal thyroid tissues. A similar pattern of expression was observed for RET51. In addition, RET51 was significantly more expressed than RET9 in MTC, while RET9 was the predominant isoform in PHEO. CONCLUSIONS: Our study documented the expression of the RET9 and RET51 isoforms in normal thyroid and PTC tissues. RET9 and RET51 isoforms were also present in MTC and PHEO. RET51 expression was higher than RET9 expression in MTC, while there was no difference in the expression of these two isoforms in PTC and normal thyroid tissues. RET9 was more highly expressed than RET51 in PHEOs.

Clinical utility of genetic diagnosis for sporadic and hereditary medullary thyroid carcinoma.

Medullary thyroid cancer (MTC) is a rare thyroid tumor whose prevalence is 3-5% among all thyroid tumors. The pathogenesis of MTC is mainly related to germline or somatic RET activating point mutations that are causative of hereditary and sporadic cases, respectively. Hereditary MTC can occur as multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial MTC (FMTC) that differ for the association with other endocrine neoplasia. Germline RET point mutations are prevalently localized in exons 5, 8, 10-11, 13-16 and a significant genotype-phenotype correlation has been observed. RET genetic screening is mandatory in all patients with a diagnosis of MTC regardless from their apparent sporadic origin. The identification of RET germline mutation in an apparently sporadic case is of great clinical utility because it allows the identification of those subjects who will develop the tumor. RET positive relatives must undergo clinical and biochemical tests to verify if the MTC is already present and, according to the type of RET mutation, they have to be screened for the presence of pheochromocytoma and/or hyperparathyroidism. If a MTC is already present patients must be surgically treated. If MTC is not yet present subjects will be followed up with basal and stimulated calcitonin serum measurement, which is the serum marker of MTC. Indeed, RET negative subjects can be reassured that they do not run any risk to develop the disease as well as their children. In conclusions RET genetic screening allows the identification of the hereditary/sporadic nature of MTC and of a relevant percentage of hidden familial MTC. Furthermore, it favors the early diagnosis of MTC in RET positive subjects. RET positive patients and no clinical evidence of MTC can be followed and surgical treatment can be delayed. Finally RET negative relatives do not need to be further monitored.

Lung Recurrence of Papillary Thyroid Cancer Diagnosed With Antithyroglobulin Antibodies After 10 Years From Initial Treatment.

Introduction: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. More than 98% of patients achieve an excellent response with no evidence of clinical, biochemical, or structural disease after initial treatment. In these patients structural recurrence is rare, more frequently diagnosed in the first 5 years from initial treatment and almost invariably localized in neck lymph nodes. Patient: We report the case of a woman affected by PTC who presented with rapidly rising anti-thyroglobulin antibodies (TgAb) level after 10 years from clinical, morphological and biochemical remission. Diagnosis and Treatment: In 2003, a 56 year old patient was treated with total thyroidectomy and radioiodine remnant ablation (RRA) for a PTC (2 cm) with minimal extrathyroidal extension (T3N1aM0 according to the 6th AJCC TNM staging system) associated with diffuse lymphocytic thyroiditis. In 2004 the patient was free of disease defined as undetectable Tg after recombinant human TSH administration in the absence of TgAb and structural disease. Since February 2012 the appearance and progressive increase of TgAb titer was observed and in 2014 a 18FDG-PET scan documented three hypermetabolic lesions suggestive of lung micrometastases. The lung lesions were cytologically confirmed as PTC metastases. Both the primary tissue and the lung metastasis were positive for BRAF V600E mutation. The patient was treated with 131-radioiodine that showed radioiodine avid lung lesions that lose the ability to take up iodine at the following treatment. The patient is still alive and the lung lesions are growing slowly. Conclusions: Structural recurrence in patients that demonstrated an excellent response after initial treatment for PTC is extremely rare, and distant metastases exceptional but possible. This case is peculiar because recurrence was early identified after 10 years from initial treatment for the presence of detectable TgAb in a patient that had an histological diagnosis of lymphocytic thyroiditis but with an atypical clinical presentation (normal thyroid at neck ultrasound and undetectable TgAb and anti-thyroid peroxidase antibodies). For this reason TgAb should be tested with Tg in patients with a history of lymphocytic thyroiditis, either histological or humoral, also when TgAb is in the normal range and not suggestive of autoimmune thyroiditis.