ABSTRACT Objective: Mutations in DICER1 are found in differentiated thyroid carcinoma (DTC) and in multinodular goiter (MNG) at a younger age with other tumors, which characterizes DICER1 syndrome. DICER1 is one driver to DTC; however, it is also found in benign nodules. We speculated that patients with mutations in DICER1 may present long-lasting MNG. Our aim was to investigate the frequency of DICER1 variants in patients with MNG. Subjects and methods: Patients who submitted to total thyroidectomy due to large MNG with symptoms were evaluated. DICER1 hotspots were sequenced from thyroid nodule samples. To confirm somatic mutation, DNA from peripheral blood was also analyzed. Results: Among 715 patients, 154 were evaluated with 56.2 ± 12.3 years old (28-79) and the thyroid volume was 115.7 ± 108 mL (16.2-730). We found 11% with six DICER1 variations in a homo or heterozygous state. Only rs12018992 was a somatic DICER1 variant. All remaining variants were synonymous and likely benign, according to the ClinVar database. The rs12018992 was previously described in an adolescent with DTC, measuring 13 mm. There were no significant differences according to gender, familial history of goiter, age, thyroid volume, TSH and TI-RADS classification between DICER1 carriers. Free T4 were lower in patients with DICER1 polymorphisms (13.77 ± 1.8 vs. 15.44 ± 2.4 pmol/L, p = 0.008), regardless of TSH levels. Conclusions: We conclude that germline DICER1 variants can be found in 11% of large goiters but no second-hit somatic mutation was found. DICER1 is one driver to thyroid lesion and a second-hit event seems unnecessary in the MNG development. Objective DICER DTC (DTC (MNG tumors syndrome however nodules longlasting long lasting methods samples analyzed Results 71 15 562 56 2 56. 123 12 3 12. 2879 28 79 (28-79 1157 115 7 115. 10 16.2730. 162730 16.2 730 . 16 (16.2-730) 11 state rs rs1201899 variant database 1 mm gender TIRADS TI RADS carriers T 13.77 1377 77 (13.7 18 8 1. vs 1544 44 15.4 24 4 2. pmolL pmol L pmol/L 0.008, 0008 0.008 , 0 008 0.008) levels Conclusions secondhit second hit development 5 287 (28-7 2730 16.2730 16273 162 16. 73 (16.2-730 rs120189 13.7 137 (13. 15. 000 0.00 00 (28- 273 16.273 1627 (16.2-73 rs12018 13. (13 0.0 (28 27 16.27 (16.2-7 rs1201 (1 0. (2 (16.2- rs120 ( (16.2 rs12 (16. rs1 (16

ABSTRACT Objective: The purpose of these guidelines is to provide specific recommendations for the surgical treatment of neck metastases in patients with papillary, follicular, and medullary thyroid carcinomas. Materials and methods: Recommendations were developed based on research of scientific articles (preferentially meta-analyses) and guidelines issued by international medical specialty societies. The American College of Physicians’ Guideline Grading System was used to determine the levels of evidence and grades of recommendations. The following questions were answered: A) Is elective neck dissection indicated in the treatment of papillary, follicular, and medullary thyroid carcinoma? B) When should central, lateral, and modified radical neck dissection be performed? C) Could molecular tests guide the extent of the neck dissection? Results/conclusion: Recommendation 1: Elective central neck dissection is not indicated in patients with cN0 well-differentiated thyroid carcinoma or in those with noninvasive T1 and T2 tumors but may be considered in T3-T4 tumors or in the presence of metastases in the lateral neck compartments. Recommendation 2: Elective central neck dissection is recommended in medullary thyroid carcinoma. Recommendation 3: Selective neck dissection of levels II–V should be indicated to treat neck metastases in papillary thyroid cancer, an approach that decreases the risk of recurrence and mortality. Recommendation 4: Compartmental neck dissection is indicated in the treatment of lymph node recurrence after elective or therapeutic neck dissection; “berry node picking” is not recommended. Recommendation 5: There are currently no recommendations regarding the use of molecular tests in guiding the extent of neck dissection in thyroid cancer. Objective follicular carcinomas methods preferentially metaanalyses meta analyses meta-analyses societies Physicians answered A B performed C Results/conclusion Resultsconclusion Results conclusion 1 cN welldifferentiated well differentiated T T3T4 TT T3 T4 T3-T compartments 2 3 IIV II V cancer mortality 4 berry picking 5 T3T

O hiperparatireoidismo (HPT) secundário tem prevalência elevada em doentes renais crônicos. Decorre de alterações na homeostase mineral, principalmente do cálcio, que estimulam as glândulas paratireoides, com aumento na secreção de paratormônio (PTH). O estímulo prolongado pode levar à autonomia na função paratireóidea. Inicialmente, o tratamento é clínico, mas a paratireoidectomia (PTx) pode ser necessária. A PTx pode ser total, subtotal e total seguida de autoimplante de tecido paratireóideo. Este trabalho compara as indicações e resultados dessas técnicas na literatura. Foi realizada revisão sistematizada dos trabalhos publicados entre janeiro de 2008 e março de 2014 sobre tratamento cirúrgico do hiperparatireoidismo secundário nas bases de dados MedLine e LILACS. Foram utilizados os termos: hiperparatireoidismo; hiperparatireoidismo secundário; glândulas paratireoides e paratireoidectomia. Foram restritos a pesquisas apenas em humanos; artigos disponíveis em meio eletrônico; publicados em português, espanhol, inglês ou francês. A amostra final foi constituída de 49 artigos. A PTx subtotal e a total mais autoimplante foram as técnicas mais utilizadas, sem consenso sobre a técnica mais efetiva. Embora haja certa preferência pela última, a escolha depende da experiência do cirurgião. Há consenso sobre a necessidade de identificar todas as paratireoides e sobre a criopreservação de tecido paratireóideo, quando possível, para enxerto em caso de hipoparatireoidismo. Exames de imagem podem ser úteis, especialmente nas recidivas. Tratamentos alternativos do HPT secundário, tanto intervencionistas quanto conservadores, carecem de estudos mais aprofundados.

Secondary hyperparathyroidism (HPT) has a high prevalence in renal patients. Secondary HPT results from disturbances in mineral homeostasis, particularly calcium, which stimulates the parathyroid glands, increasing the secretion of parathyroid hormone (PTH). Prolonged stimulation can lead to autonomy in parathyroid function. Initial treatment is clinical, but parathyroidectomy (PTx) may be required. PTx can be subtotal or total followed or not followed by parathyroid tissue autograft. We compared the indications and results of these strategies as shown in the literature through a systematic literature review on surgical treatment of secondary HPT presented in MedLine and LILACS from January 2008 to March 2014. The search terms were: hyperparathyroidism; secondary hyperparathyroidism; parathyroidectomy and parathyroid glands, restricted to research only in humans, articles available in electronic media, published in Portuguese, Spanish, English or French. We selected 49 articles. Subtotal and total PTx followed by parathyroid tissue autograft were the most used techniques, without consensus on the most effective surgical procedure, although there was a preference for the latter. The choice depends on surgeon’s experience. There was consensus on the need to identify all parathyroid glands and cryopreservation of parathyroid tissue whenever possible to graft if hypoparathyroidism arise. Imaging studies may be useful, especially in recurrences. Alternative treatments of secondary HPT, both interventional and conservative, require further study.

Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy. In a single academic center, 83 cases of hyperparathyroidism/ multiple endocrine neoplasia type 1 were operated on from 1987 to 2010 and our first surgical choice was total parathyroidectomy followed by parathyroid auto-implant to the non-dominant forearm and, since 1997, associated transcervical thymectomy to prevent thymic carcinoid. Overall, 40% of patients were given calcium replacement (mean intake 1.6 g/day) during the first months after surgery, and this fell to 28% in patients with longer follow-up. These findings indicate that several months may be needed in order to achieve a proper secretion by the parathyroid auto-implant. Hyperparathyroidism recurrence was observed in up to 15% of cases several years after the initial surgery. Thus, long-term follow-up is recommended for such cases. We conclude that, despite a tendency to subtotal parathyroidectomy worldwide, total parathyroidectomy followed by parathyroid auto-implant is a valid surgical option to treat hyperparathyroidism/multiple endocrine neoplasia type 1. Larger comparative systematic studies are needed to define the best surgical approach to hyperparathyroidism/multiple endocrine neoplasia type 1.

OBJETIVO: Comparar a quantificação da imunomarcação através de um método digital assistido por computador à bem estabelecida análise semiquantitativa. MÉTODO: A marcação citoplasmática de galectina-3 foi obtida por reações imunohistoquímicas em 25 casos de carcinoma bem-diferenciado da glândula tireóide. Determinou-se o índice de expressão da análise semiquantitativa que associa a convencional fração de área de células marcadas com os escores de intensidade da imunoexpressão, com base na observação visual qualitativa. O método digital assistido por computador foi desenvolvido com o uso de um programa de análise de imagem (ImageLab®). Três parâmetros foram obtidos: (1) porcentagem de células marcadas; (2) intensidade de imunoexpressão digital e (3) índice de expressão digital. O método proposto resulta na análise numérica da intensidade de imunoexpressão. RESULTADOS: Houve importante correlação entre as intensidades de imunoexpressão obtidas pelos dois métodos (coeficiente de correlação de Pearson, r=0,71, p=0,0001). O mesmo foi observado entre os índices de expressão (coeficiente de correlação de Pearson, r=0,66, p=0,0001). DISCUSSÃO: Os resultados de intensidade de imunoexpressão obtidos com o emprego do método digital assistido por computador foram concordantes com os escores da análise semiquantitativa. Entretanto, os resultados alcançados com o emprego do método digital podem resolver a discordância entre diferentes observadores com relação a esta intensidade de imunomarcação. Além disso, o método proposto não categoriza os resultados em grupos, o que torna a análise imunohistoquímica numericamente mensurável individualmente, aumentando seu poder diagnóstico e, sobretudo, prognóstico.

PURPOSE: To compare immunostaining quantification obtained by a digital computer-assisted method with the well-established semiquantitative analysis. METHODS: Cytoplasmic staining of galectin-3 was obtained by standard immunohistochemical reactions in 25 cases of well-differentiated thyroid carcinoma. The expression index that associates the conventional area fraction of labeled cells with the immunostaining intensity score based on visual qualitative observation was used as the semiquantitative analysis. A digital computer-assisted method is described based on the use of an image processing program (ImageLab®). Three parameters were obtained: (1) percentage of labeled cells; (2) digital immunostaining intensity, and (3) digital expression index. The proposed method allows numerical analysis of the immunostaining intensity. RESULTS: There was a strong correlation between the immunostaining intensity obtained by the two methods (Pearson correlation coefficient, r = 0.71, P = 0.0001). The same was observed between expression indexes (Pearson correlation coefficient, r = 0.66, P = 0.0001). CONCLUSION: Results obtained with our proposed digital computer-assisted method for immunoexpression analysis were concordant with the semiquantitative analysis. In addition, digital values can also resolve disagreement among different observers about the quality of staining intensity because the digital method does not classify the results into groups, but rather provides a numerical value for each individual case; thus, it increases the diagnostic and, more importantly, the prognostic sensitivity of the immunohistochemical analysis.

OBJETIVO: Analisar fatores que influenciam a ocorrência de metástase linfática cervical e a sobrevida nos tumores malignos epiteliais da glândula parótida. MÉTODO: Analisamos retrospectivamente os prontuários de 150 pacientes tratados em nossa instituição de 1974 a 1998. Vinte e quatro pacientes foram excluídos do estudo por não terem sido tratados primariamente por cirurgia. O 126 pacientes restantes foram submetidos a parotidectomia e incluídos neste estudo. Setenta e quatro pacientes tiveram sua cirurgia complementada por radioterapia pós-operatória. Trinta e quatro pacientes foram submetidos ao esvaziamento cervical associado a parotidectomia. A idade média foi de 49 anos. Todos os pacientes foram estadiados pela Classificação TNM da UICC de 1997, sendo 49 pacientes estágio I, 27 estágio II, 22 estágio III, and 28 estágio IV. A influência dos fatores analisados na ocorrência de metástase cervical foi estabelecida pelo teste do chi quadrado e por análise multivariada. A influência de fatores prognósticos na sobrevida específica de doença (SED) em 5 e 10 anos foi estabelecida pelo método de Kaplan-Meier e pelo teste log-rank. RESULTADOS: O tipo histopatológico de 40 pacientes foi o carcinoma mucoepidermóide, de 18 pacientes o adenocarcinoma (SOE), de 18 pacientes o carcinoma de células acinares, de 15 pacientes o carcinoma adenóide cístico, de 11 pacientes o carcinoma exadenoma pleomórfico, de 11 pacientes o carcinoma de ducto salivares, e de 13 pacientes outras histopatologias. Vinte e cinco pacientes apresentaram recidivas, 17 recidivas locais, quatro recidivas regionais, e quatro recidivas loco-regionais. A incidência geral de metástase linfática cervical foi de 17,5%. Metástases linfáticas cervicais ocultas ocorreram em cinco pacientes daqueles submetidos a esvaziamento cervical profilático. A presença de paralisia facial no diagnóstico, a idade, o estágio T, e o grau de malignidade foram relacionados a ocorrência de metástase linfática cervical na análise multivariada. Cinco fatores influenciaram negativamente o prognóstico, estágio T3-T4, alto grau de malignidade, presença de metástase cervical, paralisia facial no diagnóstico, e idade acima de 50 anos. A SED em 10 anos foi de 97% para o estágio I, 81% para o estágio II, 56% para o estágio III, e 20% para estágio IV. CONCLUSÕES: O grau de malignidade e o estágio foram os fatores prognósticos mais importantes. Apesar de ser um estudo retrospectivo e não randomizado, nossos dados sugerem que o esvaziamento cervical profilático deve ser considerado em casos de tumores de alto grau de malignidade, estágio T3-T4, e na presença de paralisia facial no diagnóstico.

BACKGROUND: Factors influencing the occurrence of neck metastasis and survival in patients with parotid malignant epithelial tumors are analyzed. METHODS: One hundred fifty patients treated at our institution from 1974 to 1998 were retrospectively reviewed. Twenty four patients were not treated by surgery and were excluded from this study. The remaining 126 patients were operated on and 74 patients had postoperative radiotherapy. Thirty four patients were treated with parotidectomy plus neck dissection. The mean age was 49 years old. According to the UICC/1997 TNM Classification 49 patients were Stage I, 27 were Stage II, 22 were Stage III, and 28 were Stage IV. The influence of selected factors on 10 years disease-specific survival was analyzed using Kaplan-Meier actuarial method and log-rank test. RESULTS: Forty patients had mucoepidermoid carcinoma, 18 patients adenocarcinoma, 18 patients acinic cell carcinoma, 15 patients adenoid cystic carcinoma, 11 patients carcinoma ex pleomorphic adenoma, 11 patients salivary duct carcinoma, and 13 patients other pathology. Recurrences occurred on 27 patients, 17 local, 4 had neck recurrences, and 4 loco-regional recurrences. Overall incidence of neck metastasis was 17.5%. Occult neck metastasis occurred in 5 patients who underwent elective neck dissection. Facial nerve dysfunction, age, T stage, grade, and histology were related to the recurrence of neck metastasis in univariate analysis. Prognoses were negatively influenced by five factors: T3- T4 stage, high malignancy grade, presence of cervical metastases, facial nerve palsy at first presentation and age higher then 50 years old. Ten years disease-specific survival was 97% for stage I, 81% for stage II, 56% for stage II, and 20% for stage IV. CONCLUSION: Tumor grade and stage were the most important prognostic factors. In spite of lack of prospective randomized published studies, recommendations to do elective neck dissections in high grade tumors, T3- T4 stage tumors, and facial nerve palsy at presentation should be considered.

CONTEXTO E OBJETIVO: A abordagem adequada do carcinoma de paratireóide parece relacionada à capacidade de identificação pelo cirurgião na primeira operação. O objetivo do estudo foi avaliar o papel da suspeita clínica pré-operatória na abordagem do carcinoma de paratireóide. TIPO DE ESTUDO E LOCAL: Análise retrospectiva realizada no Departamento de Cirurgia de Cabeça e Pescoço, da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil. MÉTODOS: De 1995 a 2000, 143 pacientes foram operados por hiperparatireoidismo. Esses casos foram revistos para verificar se a suspeita clínica pré e intra-operatória de carcinoma de paratireóide foi útil para a realização de operação mais extensa e quais fatores melhor se relacionaram com a suspeita de carcinoma. RESULTADOS: Entre 66 casos de hiperparatireoidismo primário, houve quatro casos de carcinoma de paratireóide (6,1%), e um caso foi encontrado em hiperparatireoidismo secundário (1,3%). Nódulos palpáveis foram observados em cinco pacientes com hiperparatireoidismo primário, quatro deles com carcinoma de paratireóide. Os níveis pré-operatórios da calcemia nos casos de carcinoma de paratireóide de hiperparatireoidismo primário variaram entre 12,0 mg/dl e 18,2 mg/dl. Em dois pacientes, o tumor tinha invasão macroscópica de estruturas adjacentes. Com exceção de um caso, com doença extensa, houve ressecção completa em monobloco dos tumores. No hiperparatireoidismo secundário, o carcinoma de paratireóide foi identificado numa quinta glândula mediastinal. Houve um caso de adenoma atípico. CONCLUSÕES: O nível de calcemia muito elevado, o tumor palpável e a aderência a estruturas próximas são comuns no carcinoma de paratireóide. Esses sinais clínicos podem ser úteis na tomada de decisão nas operações sobre a glândula paratireóide.

CONTEXT AND OBJECTIVE: Adequate management of parathyroid carcinoma apparently relates to the surgeon’s ability to identify it at the first operation. The objective of this paper was to evaluate the role of clinical suspicion in the management of parathyroid carcinoma. DESIGN AND SETTING: Retrospective analysis of parathyroid carcinoma patients treated in Department of Head and Neck Surgery, Faculdade de Medicina da Universidade de São Paulo. METHODS: Cross-sectional study of 143 patients who underwent surgery from 1995 to 2000, due to hyperparathyroidism. These cases were reviewed to ascertain whether preoperative and intraoperative suspicion of parathyroid carcinoma were helpful during the operation, and which factors demonstrated the suspicion of cancer best. RESULTS: Among 66 patients with primary hyperparathyroidism there were four cases of parathyroid carcinoma (6.1%), and one case was found in secondary hyperparathyroidism (1.3%). Palpable nodules were found in five patients with primary hyperparathyroidism, four of them with parathyroid carcinoma. Preoperative levels of calcium in primary hyperparathyroidism with cancer patients varied from 12.0 mg/dl to 18.2 mg/dl. Two patients had gross macroscopic spread of the tumor to adjacent structures. Except for one patient, with extensive disease, tumors were resected en bloc. In secondary hyperparathyroidism, parathyroid carcinoma was found in a fifth mediastinal gland. One atypical adenoma was observed. CONCLUSIONS: High levels of calcium, palpable tumors and adherence to close structures are more common in parathyroid carcinoma. These clinical signs may be helpful for decision-making during parathyroid surgery.

O desenvolvimento dos tumores depende da formação de neovasos, a angiogênese. Em algumas neoplasias, a alta densidade de microvasos tumorais correlaciona-se com a presença de metástase. OBJETIVO: Determinar se a medida da angiogênese pode indicar o potencial de metástase e o prognóstico do carcinoma papilífero tireóideo. MÉTODO: Foi feita análise retrospectiva de 30 tireoidectomizados, divididos em dois grupos de 15 indivíduos cada, respectivamente com e sem metástase. A partir dos blocos de parafina, foi calculada a densidade de microvasos no tecido tumoral por meio da quantificação da expressão do anticorpo CD34 pela imunohistoquímica. A associação da densidade de microvasos com a presença de metástase, ocorrência de recidiva e os grupos de risco do índice prognóstico AMES foi determinada por análise estatística. RESULTADOS: A mediana da densidade de microvasos no grupo de doentes sem metástase (200,0 microvasos/mm²) foi inferior àquela dos portadores de metástase (254,4 microvasos/mm²) (p = .2), sem atingir significância estatística. Ao considerar apenas os subtipos histológicos clássico e de células altas, essa diferença tornou-se significante (p = .02), uma vez que a variante folicular exibiu maior DMV que os demais subtipos, independente da presença de metástase. Houve tendência não significativa à maior densidade de microvasos entre aqueles que apresentaram recidiva (294,4 microvasos/mm² contra 249,6 microvasos/mm², p = .11). Nos grupos de baixo e alto risco, a mediana da densidade de microvasos foi de 304,0 microvasos/mm² e 229,6 microvasos/mm² respectivamente (p = .27). CONCLUSÃO: A angiogênese foi mais intensa nos tumores com metástase nos subtipos clássico e de células altas, sugerindo que a contagem de microvasos pode ser um indicador do potencial de metástase nestes subtipos histológicos do carcinoma papilífero tireóideo. Doentes que evoluíram com recidiva tenderam a exibir maior angiogênese, porém não houve associação da densidade de microvasos e o índice prognóstico.

Angiogenesis is new blood vessel formation, a process that can lead to tumor development. Microvessel count has been correlated to metastasis in some neoplasias. PURPOSE: To determine if measurement of microvessel density is useful in predicting metastasis to the cervical lymph node and prognosis in patients with papillary thyroid carcinoma. METHODS: A retrospective analysis was performed in 30 patients that had undergone total thyroidectomy. They were divided in 2 groups of 15 patients - with and without metastatic disease. Immunohistochemistry was used to detect expression of CD34 in archival paraffin-embedded papillary thyroid tumors, and microvessel density was calculated based on it. Association between microvessel density and the presence of metastasis, according to histological subtype, disease recurrence, and AMES prognostic index groups was determined through statistical analysis. RESULTS: The median microvessel density for the patient group without metastasis (200.0 microvessels/mm²) was apparently, but not significantly, less than that observed among metastatic disease patients (254.4 microvessels/mm²) (P = .20). When papillary carcinoma subtypes were analyzed, this difference became significant (P =.02). The follicular variant exhibited a greater microvessel density than the other subtypes, independent of metastasis presence. There was an apparent, but not significant, tendency for a larger median microvessel density in the group of patients that presented recurrence (294.4 microvessels/mm² vs 249.6 microvessels/mm², P = .11). There was no relationship between risk level and microvessel density: in the low- and high-risk groups, the median MVD was 304.0 microvessels/mm² and 229.6 microvessels/mm², respectively (P = .27). CONCLUSIONS: The results suggest that angiogenesis is more intense among metastatic tumors in the classic and the tall cell variants, indicating that microvessel count can be an indicator of the potential for metastasis in these subtypes of papillary thyroid carcinoma. Patients that developed recurrent disease had a tendency to exhibit higher angiogenesis; however, there was no association between microvessel density and the AMES prognostic index.