Non-invasive follicular neoplasm with papillary-like nuclear features: a challenging and infrequent entity in Argentina.

PURPOSE: Non-invasive encapsulated follicular variant of papillary thyroid cancer was reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). These neoplasms have an extremely low malignant potential. The aim of this study was (1) to assess the prevalence of NIFTP in patients with papillary thyroid carcinoma, (2) to evaluate their outcomes, and (3) to determine their molecular profile. METHODS: Multicenter, descriptive, retrospective study. Patients with papillary thyroid cancer diagnosed from January 2006 to December 2016 from 11 referral centers were included. Diagnosis of NIFTP was based on criteria described by Nikiforov et al. in 2018. At least two pathologists agreed on the diagnosis. Two thousand six hundred and seventy-seven papillary thyroid cancer patients were included; 456 (17%) of them were follicular variant papillary thyroid cancer, and 30 (1.12%) fulfilled diagnostic criteria for NIFTP. RESULTS: Each of the 30 included patients underwent a total thyroidectomy, and 50% were treated with radioiodine (median dose 100 mCi). After a median follow-up of 37 months, 84% of patients had an excellent response, 3% had an indeterminate response and data was missing in the remaining 13%. No metastatic lymph nodes, distant metastases or recurrences were found. RAS mutations were detected in 4 patients (13%). CONCLUSION: The prevalence of NIFTP in our series is amongst the lowest reported. Excellent outcomes of patients underscore their low malignant potential. Molecular findings differ from other series, probably related to environmental or ethnic features of our population and the meticulous criteria for diagnosing NIFTP.

Testing of mutations on thyroid nodules with indeterminate cytology: A prospective study of 112 patients in Argentina.

BACKGROUND: The study of genetic mutations in thyroid nodules makes it possible to improve the preoperative diagnosis of and reduce unnecessary surgeries on benign nodules. In this study, we analysed the impact of implementing a 7-gene mutation panel that enables mutations to be detected in BRAF and RAS (H/N/K) and the gene fusions PAX8/PPARG, RET/PTC1 and RET/PTC2, in a population in northern Argentina. METHODS: We performed a prospective analysis of 112 fine needle aspirations diagnosed as having indeterminate cytology according to the Bethesda classification system. These include the Bethesda III or atypia of unknown significance/follicular lesion of unknown significance and Bethesda IV or follicular neoplasm/suspicious for follicular neoplasm categories. The mutations of the 7-gene panel were analysed and this information was linked to the available histology and ultrasound monitoring. RESULTS: The BRAF V600E and RET/PTC1 mutations were associated with carcinoma in 100% of cases (n = 8), whereas only 37.5% (n = 3) of the nodules with RAS and 17% (n = 1) with PAX8/PPARG mutations were associated with carcinoma. From the histological diagnosis and ultrasound monitoring of patients, we can estimate that this panel has a sensitivity of 86% in detecting malignant carcinoma, a specificity of 77%, a positive predictive value (PPV) of 54% and a negative predictive value (NPV) of 94%. In this study, it was possible to reduce the number of surgeries by 48% in the patients analysed. CONCLUSION: The implementation of the mutation panel allowed the appropriate surgical strategy to be selected for each patient, the number of two-step surgeries to be reduced, and active follow-up to be established in low-risk patients.

Testing of mutations on thyroid nodules with indeterminate cytology: A prospective study of 112 patients in Argentina. / Testeo de mutaciones en nódulos tiroideos con citología indeterminada: estudio prospectivo de 112 pacientes en Argentina.

BACKGROUND: The study of genetic mutations in thyroid nodules makes it possible to improve the preoperative diagnosis of and reduce unnecessary surgeries on benign nodules. In this study, we analysed the impact of implementing a 7-gene mutation panel that enables mutations to be detected in BRAF and RAS (H/N/K) and the gene fusions PAX8/PPARG, RET/PTC1 and RET/PTC2, in a population in northern Argentina. METHOD: We performed a prospective analysis of 112 fine needle aspirations diagnosed as having indeterminate cytology according to the Bethesda classification system. These include the Bethesda III or atypia of unknown significance/follicular lesion of unknown significance and Bethesda IV or follicular neoplasm/suspicious for follicular neoplasm categories. The mutations of the 7-gene panel were analysed and this information was linked to the available histology and ultrasound monitoring. RESULTS: The BRAF V600E and RET/PTC1 mutations were associated with carcinoma in 100% of cases (n=8), whereas only 37.5% (n=3) of the nodules with RAS and 17% (n=1) with PAX8/PPARG mutations were associated with carcinoma. From the histological diagnosis and ultrasound monitoring of patients, we can estimate that this panel has a sensitivity of 86% in detecting malignant carcinoma, a specificity of 77%, a positive predictive value (PPV) of 54% and a negative predictive value (NPV) of 94%. In this study, it was possible to reduce the number of surgeries by 48% in the patients analysed. CONCLUSION: The implementation of the mutation panel allowed the appropriate surgical strategy to be selected for each patient, the number of two-step surgeries to be reduced, and active follow-up to be established in low-risk patients.

Inversiones cromosómicas (anomalías estructurales poco frecuentes) asociadas a fenotipo normal, dudoso y patológico / Chromosomal inversions (Slight structural anomalies) associated to normal, doubtfull and pathological phenotypes

Las inversiones son reordenamientos intracromosómicos originados por dos rupturas en un cromosoma seguidas de la reinserción del fragmento rotado en 180º. Dependiendo si involucra o no al centrómero pueden ser pericén tricas o paracéntricas. La incidencia es 0.09 a 0.49/1.000. Las inversiones son rearreglos estructurales aparentemente equilibrados, por lo que la mayoría de los individuos portadores tienen fenotipos normales y una minoría tienen fenotipos patológicos (probablemente por alteración en la secuencia de genes o variación en la función de éstos por efectos de cambio de posición). Se presentan tres casos de inversiones detectas por la técnica de Bandeo G y confirmadas por Hibridación In Situ Fluorescente (FISH). Caso 1: INVERSION PARACENTRICA FAMILIAR DEL CROMOSOMA 13 ASOCIADA A RETRASO MENTAL Y DISMORFIAS. El exhaustivo análisis del árbol genealógico y el estudio cromosómico al mayor número posible de individuos permitió confirmar la asociación inversión/fenotipo patológico en este grupo familiar. 13 de 17 miembros son portadores de inv(13)(q31q32)inh.ish inv(13)(q31q32) (wcp13+). Caso 2: INVERSION PARACENTRICA DEL CROMOSOMA 6 DE NOVO EN RECIEN NACIDO CON RETRASO MADURATIVO GLOBAL Y RETRASO DEL CRECIMIENTO INTRAUTERINO. En este caso no es posible adjudicar que, el fenotipo afectado se deba a la inversión. Cariotipo: 46,XY,add(6)(q21)dn.ish inv(6)(q21q27)(wcp6+). Caso 3: INVERSION PERICENTRICA DEL CROMOSOMA 12 EN OVODONANTE. Dicha inversión no parece tener efecto sobre el fenotipo, ya que es una paciente con coeficiente intelectual normal y no presenta malformaciones congénitas. Cariotipo: 46,XX,inv(12)(p12q14).ish inv(12) (p12q14)(wcp12+). Este reporte de casos muestra los tres fenotipos posibles de una inversión: patológico, dudoso y normal. Es el primer reporte de una inv(13) que confiera fenotipo patológico.

The inversions are intrachromosomal rearrangements which occur when a single chromosome undergoes two breaks and the region between it's rotates 180 degrees before rejoining. Depending on whether or not it include the centromere, they can be pericentric or paracentric. The incidence is 0.09 to 0.49/1,000. The inversions are apparently balanced structural rearrangements, so the most of the carrier individuals show normal phenotypes and a minority have pathological phenotypes (probably due to variation in their function due to changes in position). Three cases of inversions detected by the G Banding technique and confirmed by Fluorescence In Situ Hybridization (FISH) are presented. Case 1: FAMILIAL PARACENTRIC INVERSION OF CHROMOSOME 13 ASSOCIATED WITH MENTAL RETARDATION AND DISMORPHIA. The exhaustive analysis of the pedigree and the chromosomal study to the greatest possible number of individuals confirmed the inversion/pathological phenotype association in this family group. 13 of 17 members are carriers of inv(13)(q31q32)inh.ish inv(13)(q31q32)(wcp13+). Case 2: PARACENTRAL INVERSION DE NOVO OF CHROMOSOME 6 IN NEWBORN WITH GLOBAL MATURITY DELAY AND DELAY OF INTRAUTERINE GROWTH. In this case it is not possible to adjudge that, the affected phenotype is due to the inversion. Karyotype: 46,XY,add(6)(q21)dn.ish inv(6)(q21q27)(wcp6+). Case 3: PERICENTRIC INVERSION OF CHROMOSOME 12 IN OVODONANT. This inversion does not seem to have an effect on the phenotype, since it is a patient with normal IQ and does not present congenital malformations. Karyotype: 46,XX,inv(12)(p12q14).ish inv(12) (p12q14)(wcp12+). This case report shows the three possible phenotypes of an inversion: pathological, questionable and normal. It is the first report of an inv(13) that confers pathological phenotype. Key words: chromosomal inversion, G Banding, phenotype, structural rearrangement, fluorescence in situ hybridization.

Genetic Imbalances in Argentinean Patients with Congenital Conotruncal Heart Defects.

Congenital conotruncal heart defects (CCHD) are a subset of serious congenital heart defects (CHD) of the cardiac outflow tracts or great arteries. Its frequency is estimated in 1/1000 live births, accounting for approximately 10⁻30% of all CHD cases. Chromosomal abnormalities and copy number variants (CNVs) contribute to the disease risk in patients with syndromic and/or non-syndromic forms. Although largely studied in several populations, their frequencies are barely reported for Latin American countries. The aim of this study was to analyze chromosomal abnormalities, 22q11 deletions, and other genomic imbalances in a group of Argentinean patients with CCHD of unknown etiology. A cohort of 219 patients with isolated CCHD or associated with other major anomalies were referred from different provinces of Argentina. Cytogenetic studies, Multiplex-Ligation-Probe-Amplification (MLPA) and fluorescent in situ hybridization (FISH) analysis were performed. No cytogenetic abnormalities were found. 22q11 deletion was found in 23.5% of the patients from our cohort, 66% only had CHD with no other major anomalies. None of the patients with transposition of the great vessels (TGV) carried the 22q11 deletion. Other 4 clinically relevant CNVs were also observed: a distal low copy repeat (LCR)D-E 22q11 duplication, and 17p13.3, 4q35 and TBX1 deletions. In summary, 25.8% of CCHD patients presented imbalances associated with the disease.