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Background: Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods: We completed a multicenter retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results: Overall, 5030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2:VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions: This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.
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Standard methods of variant assessment in hereditary cancer susceptibility genes are limited by the lack of availability of key supporting evidence. In cancer, information derived from tumors can serve as a useful source in delineating the tumor behavior and the role of germline variants in tumor progression. We have previously demonstrated the value of integrating tumor and germline findings to comprehensively assess germline variants in hereditary cancer syndromes. Building on this work, herein, we present the development and application of the INT2GRATE|HPPGL platform. INT2GRATE (INTegrated INTerpretation of GeRmline And Tumor gEnomes) is a multi-institution oncology consortium that aims to advance the integrated application of constitutional and tumor data and share the integrated variant information in publicly accessible repositories. The INT2GRATE|HPPGL platform enables automated parsing and integrated assessment of germline, tumor, and genetic findings in hereditary paraganglioma-pheochromocytoma syndromes (HPPGLs). Using INT2GRATE|HPPGL, we analyzed 8600 variants in succinate dehydrogenase (SDHx) genes and their associated clinical evidence. The integrated evidence includes germline variants in SDHx genes; clinical genetics evidence: personal and family history of HPPGL-related tumors; tumor-derived evidence: somatic inactivation of SDHx alleles, KIT and PDGFRA status in gastrointestinal stromal tumors (GISTs), multifocal or extra-adrenal tumors, and metastasis status; and immunohistochemistry staining status for SDHA and SDHB genes. After processing, 8600 variants were submitted programmatically from the INT2GRATE|HPPGL platform to ClinVar via a custom-made INT2GRATE|HPPGL variant submission schema and an application programming interface (API). This novel integrated variant assessment and data sharing in hereditary cancers aims to improve the clinical assessment of genomic variants and advance precision oncology.
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AIMS: Recently, there have been attempts to improve prognostication and therefore better guide treatment for patients with medullary thyroid carcinoma (MTC). In 2022, the International MTC Grading System (IMTCGS) was developed and validated using a multi-institutional cohort of 327 patients. The aim of the current study was to build upon the findings of the IMTCGS to develop and validate a prognostic nomogram to predict recurrence-free survival (RFS) in MTC. METHODS AND RESULTS: Data from 300 patients with MTC from five centres across the USA, Europe, and Australia were used to develop a prognostic nomogram that included the following variables: age, sex, AJCC stage, tumour size, mitotic count, necrosis, Ki67 index, lymphovascular invasion, microscopic extrathyroidal extension, and margin status. A process of 10-fold cross-validation was used to optimize the model's performance. To assess discrimination and calibration, the area-under-the-curve (AUC) of a receiver operating characteristic (ROC) curve, concordance-index (C-index), and dissimilarity index (D-index) were calculated. Finally, the model was externally validated using a separate cohort of 87 MTC patients. The model demonstrated very strong performance, with an AUC of 0.94, a C-index of 0.876, and a D-index of 19.06. When applied to the external validation cohort, the model had an AUC of 0.9. CONCLUSIONS: Using well-established clinicopathological prognostic variables, we developed and externally validated a robust multivariate prediction model for RFS in patients with resected MTC. The model demonstrates excellent predictive capability and may help guide decisions on patient management. The nomogram is freely available online at https://nomograms.shinyapps.io/MTC_ML_DFS/.
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Carcinoma Neuroendócrino , Nomogramas , Neoplasias da Glândula Tireoide , Humanos , Área Sob a Curva , Prognóstico , Neoplasias da Glândula Tireoide/diagnósticoRESUMO
Purpose: The prognostic importance of RET and RAS mutations and their relationship to clinicopathologic parameters and outcomes in medullary thyroid carcinoma (MTC) need to be clarified. Experimental Design: A multicenter retrospective cohort study was performed utilizing data from 290 patients with MTC. The molecular profile was determined and associations were examined with clinicopathologic data and outcomes. Results: RET germ line mutations were detected in 40 patients (16.3%). Somatic RET and RAS mutations occurred in 135 (46.9%) and 57 (19.8%) patients, respectively. RETM918T was the most common somatic RET mutation (n = 75). RET somatic mutations were associated with male sex, larger tumor size, advanced American Joint Committee Cancer (AJCC) stage, vascular invasion, and high International Medullary Thyroid Carcinoma Grading System (IMTCGS) grade. When compared with other RET somatic mutations, RETM918T was associated with younger age, AJCC (eighth edition) IV, vascular invasion, extrathyroidal extension, and positive margins. RET somatic or germ line mutations were significantly associated with reduced distant metastasis-free survival on univariate analysis, but there were no significant independent associations on multivariable analysis, after adjusting for tumor grade and stage. There were no significant differences in outcomes between RET somatic and RET germ line mutations, or between RETM918T and other RET mutations. Other recurrent molecular alterations included TP53 (4.2%), ARID2 (2.9%), SETD2 (2.9%), KMT2A (2.9%), and KMT2C (2.9%). Among them, TP53 mutations were associated with decreased overall survival (OS) and disease-specific survival (DSS), independently of tumor grade and AJCC stage. Conclusions: RET somatic mutations were associated with high-grade, aggressive primary tumor characteristics, and decreased distant metastatic-free survival but this relationship was not significant after accounting for tumor grade and disease stage. RETM918T was associated with aggressive primary tumors but was not independently associated with clinical outcomes. TP53 mutation may represent an adverse molecular event associated with decreased OS and DSS in MTC, but its prognostic value needs to be confirmed in future studies.
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Carcinoma Neuroendócrino , Neoplasias da Glândula Tireoide , Humanos , Masculino , Estudos Retrospectivos , Proteínas Proto-Oncogênicas c-ret/genética , Carcinoma Neuroendócrino/patologia , Neoplasias da Glândula Tireoide/patologia , Mutação , GenômicaRESUMO
PEComas are a family of mesenchymal neoplasms composed of histologically distinctive perivascular epithelioid cells which demonstrate myomelanocytic differentiation. PEComas of the adrenal gland are very rare and can represent a considerable diagnostic challenge given their morphologic overlap with more common adrenal cortical neoplasms. We present the clinicopathologic features of 7 primary adrenal PEComas. The cohort comprised 5 male and 2 female patients with a median age of 63 years (range: 31 to 71 y). One patient had Birt-Hogg-Dubé syndrome and another had Lynch syndrome; however, none had a history of tuberous sclerosis complex. Histologically, tumors showed nested and/or sheet-like growth and epithelioid cytomorphology with pale-to-eosinophilic granular cytoplasm. Two tumors had an admixed spindle cell component. There was a median of 4 mitoses per 10 HPFs (range: 0 to 8). Necrosis was present in 4 tumors and lymphovascular invasion in 1. Four tumors were classified as malignant. By immunohistochemistry, tumors were positive for HMB-45 (3/7), MITF (3/3), Melan-A (3/7), smooth muscle actin (5/7), desmin (5/7), and caldesmon (1/1). Two tumors were positive for TFE3 (2/4). Inhibin and SF1 were negative in all tumors assessed (0/6). Of 3 patients with available clinical follow-up information, 1 patient developed locally recurrent and metastatic disease (at 18 mo) and was alive with persistent disease at the last follow-up. Two patients had no recurrent or metastatic disease at the last follow-up (60 and 25 mo). Although PEComas of the adrenal gland are rare, pathologists need to be alert to this entity in the differential diagnosis of primary adrenocortical neoplasms. In suspected cases, the judicious use of melanocytic and smooth muscle markers, in addition to TFE3 and markers of adrenocortical differentiation (such as SF1 and inhibin) can assist in diagnosis. As in PEComas arising at other visceral sites, an association with tuberous sclerosis complex seems to be uncommon.
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PURPOSE: RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC). EXPERIMENTAL DESIGN: We performed a clinical-genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next-generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations. RESULTS: Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared with DTCs harboring a solitary RAS mutation, patients with DTC with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P < 0.001) and to have larger primary tumors (4.7 vs. 2.5 cm; P = 0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P < 0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%; P = 0.011) when additional mutations were identified. CONCLUSIONS: Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision-making.
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Adenocarcinoma , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Neoplasias da Glândula Tireoide/patologia , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/patologia , Prognóstico , Mutação , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Although pediatric thyroid tumors have many similarities to those occurring in adults, significant differences are also recognized. For example, although thyroid nodules in children are much less common than in adults, a higher percentage is malignant. Moreover, while pediatric papillary thyroid carcinoma (PTC) is associated with more advanced disease, death due to disease in children and adolescents is very rare, even when distant metastases are present. Some subtypes of thyroid carcinoma, like diffuse sclerosing variant, are especially common in children and adolescents. Moreover, certain histologic findings, such as a tall cell morphology or increased mitotic activity, may not carry the same prognostic significance in children as in adults. Recent studies exploring the molecular underpinnings of pediatric thyroid carcinoma indicate that while driver alterations of thyroid tumorigenesis in children and adults are essentially the same, they occur at very different frequencies, with translocation-associated tumors (most commonly harboring RET and NTRK fusions) comprising a sizable and distinct group of pediatric PTC. DICER1 mutations, an infrequent mutation in adult thyroid tumors, are relatively frequent in pediatric encapsulated follicular-patterned thyroid tumors (with or without invasion or nuclear features of PTC). Additionally, tumor predisposition syndromes (most notably DICER1 syndrome and PTEN hamartoma tumor syndromes such as Cowden syndrome) should be considered in children with thyroid tumors, especially follicular-patterned thyroid tumors and poorly differentiated thyroid carcinoma. This review will explore the current state of knowledge of thyroid nodules and carcinomas in children and adolescents.
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Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Adulto , Adolescente , Humanos , Criança , Nódulo da Glândula Tireoide/genética , Síndrome , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/genética , Câncer Papilífero da Tireoide/genética , Ribonuclease III , RNA Helicases DEAD-boxRESUMO
Background: While the diagnosis of papillary thyroid carcinomas (PTCs) with tall cell features (PTCtcf) is often made for carcinomas with histological features intermediate between classic and tall cell subtypes of PTC (tcPTC), its comparative signature to that of either tcPTC or classic PTC is less clear. The objective of this study was to perform an integrative clinicopathologic and genomic analysis elucidating the spectrum of tcPTC, PTCtcf, and classic PTC. Methods: We analyzed all consecutive patients with tcPTC and PTCtcf evaluated at a tertiary academic referral center between 2005 and 2020, as well as a comparative cohort of classic PTC, in a retrospective observational cohort analysis. Clinicopathologic data were compared among the three groups, including progression-free survival (PFS), recurrent/persistent disease, and a negative composite outcome of death, progression, or need for advanced therapy. To specifically understand differences between tcPTC and PTCtcf, targeted next-generation sequencing was performed in a subset of these cohorts. Results: A total of 292 patients were analyzed (81 tcPTC, 65 PTCtcf, 146 classic PTC). Thirteen percent of tcPTC versus 8% of PTCtcf versus 1% of classic PTC had the advanced American Joint Committee on Cancer stage (p = 0.002). Similarly, macroscopic extrathyroidal extension was observed in 38% of tcPTC, 14% of PTCtcf, and 12% of classic PTC (p < 0.001). The 5-year PFS was 76.5%, 81.5%, and 88.3% for tcPTC, PTCtcf, and classic PTC, respectively, while the rates of the negative composite outcome 40.2% for tcPTC, 20.7% for PTCtcf, and 11.2% for classic PTC (p < 0.001). In a multivariable Cox regression analysis, the negative composite outcome was independently associated with tcPTC (HR 4.3 [confidence interval 1.1-16.1], p = 0.03). tcPTC demonstrated substantially more hotspot TERT promoter mutations than PTCtcf (44% vs. 6%, p = 0.012). Conclusions: Our study demonstrates a continuum of disease-specific risk of PTC, pointing at PTCtcf as an intermediate entity between tcPTC and classic PTC. These data provide a more refined understanding of risk at time of presentation, while better elucidating the diversity of genomic drivers.
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Carcinoma Papilar , Carcinoma , Neoplasias da Glândula Tireoide , Humanos , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide/patologia , Estudos Retrospectivos , Carcinoma Papilar/patologia , Carcinoma/patologia , PrognósticoRESUMO
Thyroid pathology is notoriously fraught with high interobserver variability, and follicular-patterned tumors are among some of the most challenging to assess accurately and reproducibly. Given that encapsulated or well-circumscribed follicular-patterned tumors often have similar molecular profiles, that is, frequent RAS or RAS-like alterations, the diagnosis usually relies on histopathologic examination alone. Unfortunately, many of the features that are used for diagnosis and prognosis of these tumors have long been controversial and frequently debated topics, both due to their subjectivity and their evolving (or not yet resolved) definitions. In more recent years, the introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features has added further complexity to this discussion. In particular, the criteria and significance of nuclear features of papillary thyroid carcinoma, architectural patterns, and invasive growth still pose significant diagnostic challenges and confusion. This review explores some of the challenges in evaluating encapsulated follicular-patterned tumors, focusing on those histologic elements.
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Adenocarcinoma Folicular , Neoplasias da Glândula Tireoide , Humanos , Adenocarcinoma Folicular/diagnóstico , Adenocarcinoma Folicular/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Câncer Papilífero da Tireoide/patologia , Invasividade Neoplásica/patologiaRESUMO
BACKGROUND: Adrenocortical carcinoma (ACC) is an aggressive, rare malignancy. 2-deoxy-2-[18F]-fluoro-d-glucose positron emission tomography (FDG-PET) assesses tumor metabolism and glucose utilization. We hypothesized that higher maximum standard uptake value (SUVmax) is associated with decreased survival. METHODS: We performed a retrospective analysis of patients with ACC. Included patients (n = 26) had an FDG-PET scan available with a documentable SUVmax. Patients were dichotomized into "High" (≥8.4, n = 12) and "Low" (<8.4, n = 14) SUVmax. Univariate analysis and survival analysis were performed to compare groups. RESULTS: Demographics between groups were equivalent. The high SUVmax cohort demonstrated lower survival (median 479 days or 15.7 months) compared to the low group (median 1490 days or 48.6 months, p = .01). Log-Rank curve confirmed differences in survival (p = .007). CONCLUSIONS: Higher SUVmax was associated with significantly worse survival in ACC and may reflect a more aggressive phenotype. FDG-PET may provide clinically useful information to determine prognosis and treatment. Further studies should prospectively evaluate using FDG-PET/CT in ACC.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18 , Carcinoma Adrenocortical/diagnóstico por imagem , Estudos Retrospectivos , Glucose , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Neoplasias do Córtex Suprarrenal/diagnóstico por imagem , Compostos RadiofarmacêuticosRESUMO
Genomic profiles of tumors are often unique and represent characteristic mutational signatures defined by DNA damage or DNA repair response processes. The tumor-derived somatic information has been widely used in therapeutic applications, but it is grossly underutilized in the assessment of germline genetic variants. Here, we present a comprehensive approach for evaluating the pathogenicity of germline variants in cancer using an integrated interpretation of somatic and germline genomic data. We have previously demonstrated the utility of this integrated approach in the reassessment of pathogenic germline variants in selected cancer patients with unexpected or non-syndromic phenotypes. The application of this approach is presented in the assessment of rare variants of uncertain significance (VUS) in Lynch-related colon cancer, hereditary paraganglioma-pheochromocytoma syndrome, and Li-Fraumeni syndrome. Using this integrated method, germline VUS in PMS2, MSH6, SDHC, SHDA, and TP53 were assessed in 16 cancer patients after genetic evaluation. Comprehensive clinical criteria, somatic signature profiles, and tumor immunohistochemistry were used to re-classify VUS by upgrading or downgrading the variants to likely or unlikely actionable categories, respectively. Going forward, collation of such germline variants and creation of cross-institutional knowledgebase datasets that include integrated somatic and germline data will be crucial for the assessment of these variants in a larger cancer cohort.
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NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC.
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Carcinoma de Células Escamosas , Fatores de Transcrição , Adolescente , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Proteínas de Ciclo Celular , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Glândula Tireoide , Fatores de Transcrição/genéticaRESUMO
The new World Health Organization classification of endocrine tumors will include many updates on thyroid pathology. This summary highlights the changes that are most relevant for cytopathologists.
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Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Citodiagnóstico , Humanos , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/patologia , Organização Mundial da SaúdeRESUMO
AIMS: Biphasic hyalinizing psammomatous (BHP) renal cell carcinoma (RCC) is a newly described emerging entity within the spectrum of papillary RCC in the WHO 2022 classification. Molecular analyses have discovered that BHP RCC consistently harbour somatic mutations in the neurofibromin 2 (NF2) gene. The NF2 gene product, merlin, is known to primarily function as a tumour suppressor. Merlin protein loss correlates closely with the presence of NF2 mutations in benign and malignant tumours arising in different sites. In the present study we explored the role of merlin immunohistochemistry (IHC) in tumours within the spectrum of BHP RCC to determine the diagnostic utility of this marker. MATERIALS AND METHODS: We performed merlin IHC in 13 BHP RCC, 18 papillary RCC, 10 TFE3-translocation RCC, 15 TFEB-altered RCC (including 13 TFEB-rearranged and 2 TFEB-amplified), and 10 mucinous tubular and spindle cell carcinomas of unknown mutational status. RESULTS: Unequivocal loss of merlin expression in >90% of the tumour cells was observed in 12/13 BHP-RCC (92%), with the remaining tumour demonstrating weak focal cytoplasmic expression in ~10% of the tumour. In contrast, merlin was diffusely or multifocally expressed in all papillary RCC, TFE3-translocation RCC, and TFEB-altered RCC, as well as in 70% of mucinous tubular and spindle carcinomas. CONCLUSIONS: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC. CONCLUSIONS: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC.
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Carcinoma de Células Renais , Carcinoma , Neoplasias Renais , Neoplasias Meníngeas , Meningioma , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Carcinoma de Células Renais/patologia , Humanos , Imuno-Histoquímica , Neoplasias Renais/patologia , Neurofibromina 2/genéticaRESUMO
In the past 30 years, there has been a substantial rise in the detection of thyroid nodules. Largely asymptomatic, thyroid nodules are most often incidental findings that typically pose minimal risk. Data supporting these findings show a rapid rise in the incidental detection of thyroid nodules and cancer, but minimal effect on mortality rates, despite treatment. These data imply that historical approaches to thyroid nodule and cancer care might at times include unnecessary or excessive care. To address this issue, the past decade has witnessed an increasingly conservative approach to nodule management, seeking to individualise care and provide the most focused intervention that leads to favourable outcomes. Benign nodules can be safely monitored with minimal, or long-interval follow-up imaging. Molecular testing should be considered for cytologically indeterminate nodules because of its ability to improve preoperative cancer risk determination and reduce unnecessary surgery. The treatment of biopsy-proven malignant nodules has become increasingly nuanced, since recommendations for near-total thyroidectomy are no longer routine. Hemithyroidectomy is now commonly considered when operative intervention is favoured. Some patients with small volume, isolated cancerous nodules are safely managed non-operatively with active monitoring. In summary, modern management strategies for thyroid nodular disease seek to incorporate the growing amount of available diagnostic and prognostic data, inclusive of demographic, radiological, pathological and molecular findings. Once obtained, an individualised management plan can be effectively formulated.
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Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Humanos , Prognóstico , Estudos Retrospectivos , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/terapia , TireoidectomiaRESUMO
Grade, based on proliferative activity and tumor necrosis, has recently been shown to be prognostic in medullary thyroid carcinoma (MTC) in multivariate analysis. The aim of this study was to evaluate the interobserver reproducibility of assessed grade in MTC. Three groups (each group included one resident/fellow and one attending pathologist) independently evaluated a cohort of 44 sporadic MTC. For each case, all available tumor slides were reviewed, and mitotic count and the presence of tumor necrosis were recorded. Ki-67 was performed, and the Ki-67 proliferative index was determined in the area of highest proliferative activity. Tumors were graded according to the recently published International Medullary Thyroid Carcinoma Grading System (IMTCGS). Kappa statistics were calculated for each individual criterion (mitotic count, Ki-67 proliferative index, and necrosis) and for assigned IMTCGS grade. For our cohort of 44 MTCs, the kappa statistic for mitotic count, Ki-67 proliferative index, and necrosis was 0.68, 0.86, and 0.89, respectively. The kappa statistic for assigned IMTCGS grade was 0.87. Our findings indicate that there was a strong level of agreement for assessment of grade in our cohort of MTC, indicating that grade as assessed by the IMTCGS is not only prognostic but also reproducible.
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Neoplasias da Glândula Tireoide , Carcinoma Neuroendócrino , Humanos , Antígeno Ki-67 , Necrose , Gradação de Tumores , Reprodutibilidade dos TestesRESUMO
AIMS: Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment. METHODS AND RESULTS: All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform and/or solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46%; 9 of 68, 13% and 6 of 62, 9%, respectively; P < 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2/MSH6 and MLH1/PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2::ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN. CONCLUSIONS: MMR deficiency was most commonly secondary to inactivation of MSH2/MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry.
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Neoplasias Colorretais , Neoplasias da Próstata , Neoplasias Encefálicas , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/genética , Humanos , Masculino , Instabilidade de Microssatélites , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Recidiva Local de Neoplasia , Síndromes Neoplásicas Hereditárias , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
DICER1 syndrome is an autosomal dominant tumor predisposition syndrome caused by germline DICER1 mutations. In the thyroid, DICER1 syndrome is associated with early-onset multinodular goiter and thyroid carcinomas. Subsequent studies have shown that somatic DICER1 mutations, though rare, can occur in follicular-patterned thyroid tumors, such as follicular adenomas and follicular thyroid carcinomas, with a higher rate seen in pediatric follicular thyroid carcinomas and in follicular thyroid carcinomas with a macrofollicular architecture. Somatic DICER1 mutations have also been reported in pediatric papillary thyroid carcinomas lacking other alterations typically associated with thyroid tumorigenesis. Although thyroid carcinomas with underlying DICER1 mutations are usually indolent, recent studies have shown that pediatric poorly differentiated thyroid carcinoma and thyroblastoma, both aggressive tumors, also harbor DICER1 mutations. This review will discuss mechanisms of DICER1 tumorigenesis and describe thyroid tumors associated with germline and somatic DICER1 mutations.