Thyroid Fine Needle Aspiration, the Bethesda System, and the BRAFV600E Mutation in Papillary Thyroid Carcinoma: Association and Prediction for Biopsy.

INTRODUCTION: BRAFV600E mutations have been associated with papillary thyroid carcinoma (PTC) histological types including tall-cell and classical, peritumoral infiltration, and nuclear signs, whereas cytological features such as plump cells and sickle nuclei have also been associated with favorable thyroid fine needle aspiration (FNA) results for this tumor. BRAF and RAS are considered early driver mutations that contribute to the development of BRAF-like PTCs and RAS-like PTCs. Our aim was to assess the possible association between all Bethesda System cytological features and thyroid FNAs for PTC and their potential predictive value for future BRAFV600E-related biopsies. METHODS: Our study analyzed 63 cases of PTCs operated on at our hospital over a 5-year period between 2005 and 2017 that had previously undergone FNA and had been classified by the Bethesda System. BRAFV600E was identified by pyrosequencing paraffin-embedded tissues and comparing the cytological signs with the Bethesda System. In addition, a statistical and predictive study of the diagnostic factors "non-follicular," "non-round nuclei," and "non-clear chromatin" was performed to discriminate BRAF-like signs from other hypothetical RAS-like follicular signs. RESULTS: BRAFV600E was detected in 43/63 cases (68.2%). Histological types were significant (p < 0.001), with the classical variant being the most prevalent 31/63 (49.2%) and independent by multivariate analysis odds ratio of 10.58 [2.67; 41.97]. Follicular cytological signs are negatively associated with BRAFV600E: follicular structure (p < 0.001), round nuclei (p = 0.015), and clear chromatin (p = 0.049), while the diagnostic factors: "non-follicular" (positive predictive value [PPV] 82.9, sensitivity 79.1, negative predictive value [NPV] 59.1, specificity 65.0), "non-round nuclei" (PPV 76.6, sensitivity 83.7, NPV 56.3, specificity 45.0), and "non-clear chromatin" (PPV 75.6, sensitivity 79.1, NPV 50.0, specificity 45.0) have predictive value for the mutation. There was no individual significance for the remaining cytological features. CONCLUSIONS: Our study found no association between cytomorphological signs of thyroid FNA and BRAFV600E mutation. Considering the Bethesda System, there is an association (p = 0.045) with numerous cases of mutated PTC in categories V and VI. Our results indicate, however, that the presence of signs referred to as "non-follicular," "non-round nuclei," and "non-clear chromatin" in biopsy of papillary thyroid carcinoma is predictive of BRAF type mutation, whereas follicular signs indicate a RAS type PTC, according to published literature. These results need to be confirmed or modified by further research.

[Gastric metastases with a choriocarcinoma component from a postpuberal teratoma with mature histology]. / Metástasis gástricas con componente de coriocarcinoma de un teratoma testicular pospuberal con histología madura.

Germ cell tumors are the most frequent neoplasia in young males. The aims of this study is to describe a case in which a postpuberal teratoma suffers a transformation to choriocarcinoma and metastasize to stomach. We have made a systematic review in PubMed and consensus documents to study this mismatch between the tumour, metastasis and the exception of gastric metastatic affectation. We describe three options to explain this discordance: a mixed germ cells tumour, a burned out tumour or a germ cells tumour derived from a malignant germ cell tumour precursor or different clonal strains. After made a thorough investigation we conclude that the most truly option is the last one as we extensive explain below. Once the gastric metastatic lesions are extremely rare and reach to <5%, but there are not conclusive assessments.

Molecular diagnosis in non-small-cell lung cancer: expert opinion on ALK and ROS1 testing.

The effectiveness of targeted therapies with tyrosine kinase inhibitors in non-small-cell lung cancer (NSCLC) depends on the accurate determination of the genomic status of the tumour. For this reason, molecular analyses to detect genetic rearrangements in some genes (ie, ALK, ROS1, RET and NTRK) have become standard in patients with advanced disease. Since immunohistochemistry is easier to implement and interpret, it is normally used as the screening procedure, while fluorescence in situ hybridisation (FISH) is used to confirm the rearrangement and decide on ambiguous immunostainings. Although FISH is considered the most sensitive method for the detection of ALK and ROS1 rearrangements, the interpretation of results requires detailed guidelines. In this review, we discuss the various technologies available to evaluate ALK and ROS1 genomic rearrangements using these techniques. Other techniques such as real-time PCR and next-generation sequencing have been developed recently to evaluate ALK and ROS1 gene rearrangements, but some limitations prevent their full implementation in the clinical setting. Similarly, liquid biopsies have the potential to change the treatment of patients with advanced lung cancer, but further research is required before this technology can be applied in routine clinical practice. We discuss the technical requirements of laboratories in the light of quality assurance programmes. Finally, we review the recent updates made to the guidelines for the determination of molecular biomarkers in patients with NSCLC.

The Iberian pig fed with high-fat diet: a model of renal disease in obesity and metabolic syndrome.

BACKGROUND: The pathogenesis of renal disease in the context of overweight/obesity, metabolic syndrome, and insulin resistance is not completely understood. This may be due to the lack of a definitive animal model of disease, which limits our understanding of obesity-induced renal damage. We evaluated the changes in renal histology and lipid deposits induced by obesity in a model of insulin resistance: the Iberian swine fed with fat-enriched food. METHODS: Twenty-eight female sows were randomized to standard (SD) or high-fat diet (HFD: 6.8% of saturated fat) for 100 days. Weight, adiposity, analytics, oral glucose tolerance tests, and measured renal function were determined. Renal histology and lipid deposits in renal tissue were analyzed. RESULTS: Animals on HFD developed obesity, hypertension, high levels of LDL cholesterol, triglycerides, insulin resistance, and glomerular hyperfiltration. No animal developed overt diabetes. Animals on HFD showed "diabetoid changes", including mesangial expansion [21.40% ± 4 vs.13.20% ± 4.0, p < 0.0001], nodular glomerulosclerosis [7.40% ± 7, 0.75 vs. 2.40% ± 4.7, p = 0.02], and glomerulomegaly (18% vs. 10%, p = 0.010) than those on SD. Tubular atrophy, interstitial fibrosis, inflammation, arteriolar hyalinosis, or fibrointimal thickening were mild and similar between groups. Triglyceride content in renal tissue was higher in animals on HFD than in SD (15.4% ± 0.5 vs. 12.7% ± 0.7; p < 0.01). CONCLUSIONS: Iberian pigs fed with fat-enriched food showed diabetoid changes and glomerulomegaly as observed in obese humans making this model suitable to study obesity-induced renal disease.

MTHFR C677T polymorphism and anatomopathological characteristics with prognostic significance in sporadic colorectal cancer.

Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis due to its role in DNA methylation, repair and synthesis. The MTHFR C677T polymorphism is associated with decreased risk of CRC and increased sensitivity to 5-FU treatment. The present study addressed the relationship between this polymorphism and histopathological and immunohistochemical characteristics of prognostic significance in 50 patients from the Canary Islands. No differences were found between the MTHFR C677T genotypes with respect to tumor budding, tumor necrosis, desmoplastic fibrosis and tumoral eosinophilia. No significant differences were found in Ki-67, bcl-2 (cytoplasmic and nuclear), CD31, CD3+ T lymphocytes (both stromal and intraepithelial) and peritumoral CD20+ B lymphocytes. In carriers of the MTHFR CC variant, tumor margins were infiltrative more frequently (68.7%) than in CT+TT carriers (33.3%, p=0.03). In addition, wild-type CC genotype showed stromal CD20+ B lymphocytes (68.8%) more often than CT+TT carriers (33.3%, p=0.03). Both parameters indicate a better tumor prognosis when the MTHFR 677T variant is present.

Clinicopathological analysis of factors related to colorectal tumor perforation: influence of angiogenesis.

Colorectal tumor perforation is a life-threatening complication of this disease. However, little is known about the anatomopathological factors or pathophysiologic mechanisms involved. Pathological and immunohistochemical analysis of factors related with tumoral neo-angiogenesis, which could influence tumor perforation are assessed in this study. A retrospective study of patients with perforated colon tumors (Group P) and T4a nonperforated (controls) was conducted between 2001 and 2010. Histological variables (differentiation, vascular invasion, and location) and immunohistochemical (CD31, Growth Endothelial Vascular Factor (VEGF) and p53) related with tumor angiogenesis were analyzed. Of 2189 patients, 100 (4.56%) met the inclusion criteria. Of these, 49 patients had nonperforated (2.23%) and 51 had perforated tumors (2.32%). The P group had lower number of right-sided tumors (7/51, 13.7%) compared with controls (13/49, 36.7%) (P = .01). The high-grade tumors (undifferentiated) represented only 3.9% of the perforated tumors; the remaining 96.1% were well differentiated (P = .01). No differences between groups in the frequency of TP53 mutation or VEGF and CD31 expression were found. In the P group, only 2 (3.9%) had vascular invasion (P = .01). Of the 12 tumors with vascular invasion, only 2 were perforated (16.6%). The median number of metastatic lymph-nodes in P Group was 0 versus 3 in controls (Z = -4.2; P < .01). Pathological analysis of variables that indirectly measure the presence of tumor angiogenesis (differentiation, vascular invasion, and the number of metastatic lymph nodes) shows a relationship between this and the perforation, location, and tumor differentiation. We could not directly validate our hypothesis, by immunohistochemistry of TP53, VEGF, and CD31, that perforated tumors exhibit less angiogenesis.

Impact of the MTHFR C677T polymorphism on colorectal cancer in a population with low genetic variability.

PURPOSES: Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis by its role in DNA methylation, repair, and synthesis. We analyzed the impact of MTHFR C677T polymorphism in colorectal cancer in a region of the Tenerife Island whose population has a history of genetic isolation and a low genetic variability. This allows analyzing the effects of the polymorphism that are not due to interactions with different genetic variants. METHODS: Genomic DNA of 50 Spanish sporadic colorectal cancer (CRC) patients and 103 controls was analyzed by PCR/RFLP and sequencing. RESULTS: The T allele is more frequent in controls than in patients (P < 0.01). The variant (T) carriers displayed significant odds ratio values for the CT heterozygotes (P = 0.026) and even when grouping heterozygote (CT) and homozygotes (TT) (P = 0.015). Patients carriers of the variant T (CT y TT) show a higher survival rate after chemotherapy than the CC homozygotes (log rank; P = 0.001). CONCLUSIONS: The MTHRF C677T variant has a protective effect on CRC development in a population with low allelic variability and an optimal intake of folic acid. Moreover, patients carrying the variant (T) show a better prognosis after 5-fluorouracil/folinic acid-based chemotherapy.

Nefropatología molecular / Molecular nephropathology

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